Accepted Manuscript

Protective effects of green tea and its main constituents against natural and chemical
toxins: A comprehensive review

Maryam Rameshrad, Bibi Marjan Razavi, Hossein Hosseinzadeh

PII: S0278-6915(16)30453-7
DOI: 10.1016/j.fct.2016.11.035
Reference: FCT 8807

To appear in: Food and Chemical Toxicology

Received Date: 25 September 2016

Revised Date: 24 November 2016
Accepted Date: 30 November 2016

Please cite this article as: Rameshrad, M., Razavi, B.M., Hosseinzadeh, H., Protective effects of green
tea and its main constituents against natural and chemical toxins: A comprehensive review, Food and
Chemical Toxicology (2016), doi: 10.1016/j.fct.2016.11.035.

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 ACCEPTED MANUSCRIPT

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Protective effects of green tea and its main constituents against natural and chemical toxins: a

comprehensive review

Maryam Rameshrada, Bibi Marjan Razavib, Hossein Hosseinzadehc

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Department of Pharmacodynamics and Toxicology, Pharmaceutical Research Center, School of Pharmacy,

Mashhad University of Medical Sciences, Mashhad, Iran, mrameshrad@gmail.com

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Targeted Drug Delivery Research Center, Department of Pharmacodynamy and Toxicology, School of

Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran, RazaviMr@mums.ac.ir

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c
Corresponding author: Department of Pharmacodynamics and Toxicology, Pharmaceutical Research Center,

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School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran, Tel.: +98 51 38819042; fax: +98

51 38823251, E-mail address: hosseinzadehh@mums.ac.ir

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Abbreviations:

A amyloid

AFB aflatoxin B1

AFB-NAC aflatoxin B1mercapturic acid

AFM1 aflatoxin M1

Al aluminum

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ALP alkaline phosphatase

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ALT alanine aminotransferase

APAP acetaminophen (N-acetyl-p-aminophenol)

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AST aspartate aminotransferase

AZA azathioprine

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B.I.D twice daily AN
C catechin

CAT catalase

Cd2+ cadmium
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CHL chinese hamster lung cells

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CNPs copper nanoparticles

COX-2 cyclooxygenase-2
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DDT dichlorodiphenyltrichloroethane

D-GalN d-Galactosamine
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DON deoxynivalenol

Dox doxorubicin
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EC epicatechin
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ECG epicatechin gallate

EGC epigallocatechin

EGCG epigallocatechin gallate

ERK1/2 extracellular signal-regulated protein kinases 1 and 2

ET-1 endothelin-1

F fluoride
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FDA food and drug administration

GC gallocatechin

GCG gallocatechin gallate

GPx glutathione peroxidase

GSH gluthathione

GT green tea

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GTP green tea polyphenols

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HgCl2 Mercury(II) chloride

i.p. intraperitoneal

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ISO isoproterenol

i.v. intravenous

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LDH lactate dehydrogenase
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LLC-PK1 pig kidney cell line

L-NAME L-NG-Nitroarginine methyl ester

LPS lipopolysaccharide
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67LR 67-kDa laminin receptor

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MAPKs mitogen-activated protein kinases

MC-LR microcystin-LR
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MDA malondialdehyde

MPP 1-methyl-4-phenylpyridinium
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mPT methyl parathion

MPTP n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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nAChR nicotinic acetylcholine receptors

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NF-B nuclear factor-kB

NMDA receptor n-methyl-D-aspartate receptor

nNOS neuronal Nitric oxide synthase

NOS nitric oxide synthase

2-NP 2-nitropropane

3-NPA 3-nitropropionic acid

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4-NQO 4-nitroquinoline1-oxide

6-OHDA 6-hydroxydopamine

OTA ochratoxin A

PAT patulin

Pb lead

PGE2 prostaglandin E2

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PI3K phosphoinositide 3-kinase

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PKC protein kinase C

PLA2s phospholipases A2

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PQ paraquat

ROS reactive oxygen species

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s.c. subcutaneous
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SOD superoxide dismutase

TBARS thiobarbituric acid reactive substances

Tlr4 toll-like receptor 4

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WHO world health organization

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Abstract:

Toxins are natural or chemical poisonous substances with severe side effects on health. Humans are generally

exposed by widespread toxic contaminations via air, soil, water, food, fruits and vegetables. Determining a

critical antidote agent with extensive effects on different toxins is an ultimate goal for all toxicologists.

Traditional medicine is currently perceived as a safe and natural approach against toxins. In this regard, we

focused on the protective effects of green tea (Camellia sinensis) and its main components such as catechin,

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epicatechin, epicatechin gallate, gallocatechin, epigallocatechin and epigallocatechin gallate as a principal

source of antioxidants against both natural and chemical toxins. This literate review demonstrates that protective

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effects of green tea and its constituents were mainly attributed to their anti-oxidative, radical scavenging,

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chelating, anti-apoptotic properties and modulating inflammatory responses. Although, some studies reveal they

have protective effects by increasing toxin metabolism and neutralizing PLA2, proteases, hyaluronidase and l-

amino acid oxidase enzymes.

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Keywords: Green tea, Camellia sinensis, Toxin, Antidote, protective, epigallocatechin gallate.
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1. Introduction

2. Methods

3. Natural toxins

3.1. Mycotoxins

3.1.1. Aflatoxin

3.1.2. Patulin

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3.1.3. Deoxynivalenol

3.1.4. Three-nitropropanoic acid

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3.1.5. Ochratoxin A

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3.2. Snake venoms

3.3. Bacterial toxins

3.3.1. Botulinum

3.3.2. Lipopolysaccharide
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3.3.3. Microcystin-LR

3.4. Other natural toxins

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3.4.1. D-Galactosamine

3.4.2. Khat
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4. Chemical induced toxicity

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4.1. Metals

4.1.1. Aluminum
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4.1.2. Arsenic

4.1.3. Cadmium
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4.1.4. Copper
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4.1.5. Mercuric

4.1.6. Lead

4.1.7. The other heavy metals

4.2. Fluoride

4.3. Pesticides

4.3.1. Chlorpyrifos

4.3.2. Cyromazine
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4.3.3. Diazinon

4.3.4. Deltamethrin

4.3.5. Dieldrin

4.3.6. Malathion

4.3.7. Methyl parathion

4.3.8. Paraquat

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4.3.9. Rotenone

4.4. Protective effects of GT and respective components against cardiotoxic xenobiotic

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4.4.1. Anthracyclines

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4.4.2. Isoproterenol

4.4.3. The other cardiotoxic agents

4.5. Protective effects of GT and respective components against neurotoxic agents

4.5.1. Glutamate
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4.5.2. N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

4.5.3. Six-hydroxydopamine
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4.5.4. Amyloid

4.5.5. Acrylamide
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4.5.6. The other neurotoxic agents

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4.6. Protective effects of GT and derived components against hepatotoxic xenobiotic

4.6.1. Acetaminophen
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4.6.2. Doxorubicin

4.6.3. Halothane
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4.6.4. Azathioprine
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4.6.5. Ethanol

4.6.6. Carbon tetrachloride

4.6.7. Vinylidene chloride

4.6.8. 2-Nitropropane

4.6.9. 1,4-naphthoquinone

4.6.10. Dextran sulfate sodium

4.6.11. Formaldehyde
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4.6.12. 4-Nitroquinoline-1-oxide

4.6.13. The other hepatotoxic agents

4.7. Protective effects of GT and its main components against nephrotoxic xenobiotic

4.7.1. Gentamycin

4.7.2. Cisplatin

4.7.3. Cyclosporine

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4.7.4. Tacrolimus

5. Clinical studies

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6. Conclusion

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Conflict of interest

References

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Introduction

Humans are exposed to widespread form of toxins via many different direct or indirect pathways. Air,

water, soil, foods, fruits, vegetables and also animals are the main exposure pathways. Toxins could be

categorized to natural, produced from living cells, and chemical agents. They have hazardous effects on human

health which could be divided to two main categories: non-organ directed toxicity, carcinogenesis, genetic and

developmental toxicity, and directed organ toxicity on liver, kidney, skin, nervous system, blood, heart and

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vascular system, immune system, respiratory system, ocular and visual system, reproductive system and

endocrine system.

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It is clear that there is a great scope for drug discovery from traditional medicines. In fact, these days

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plants have an important role in Western medicine as alternative sources of drugs for treating some diseases [1].

Tea plant, Camellia sinensis (Theaceae) [2], is originated from Southeast Asia and currently cultivated

in more than 30 countries, including India, China, Sri Lanka, Kenya, Indonesia, Turkey, former Soviet Union,

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Japan, Iran, Bangladesh, Malawi, Vietnam and Argentina [3]. It has been reported that tea is the most popular
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beverage, after water, around the world [3]. There are at least three basic forms of tea, including green, black

and oolong tea. Green tea (GT) is generally made while polyphenol ingredient of green leaf, also known as
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catechin, do not begin to wilt and oxidize [2]. GT leafs contain various components including polyphenols (36%

of dry weight), methylxanthines (3.5%), amino acids (4%), organic acids (1.5%), carotenoids (<0.1%), volatiles
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(0.1%), carbohydrates (25%), protein (15%), lignin (6.5%), lipids (2%), ash (5%), chlorophyll and small amount
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of the other substances (0.5%), although the percentage of these ingredients could be changed by season,

climate, horticultural practices and age of the leaf [3]. The major GT polyphenol belongs to the family of
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catechins. This family comprises epigallocatechin gallate (EGCG), catechin (C), epicatechin (EC), gallocatechin

(GC), gallocatechin gallate (GCG), epigallocatechin (EGC), and epicatechin gallate (ECG) (Figure 1) [4]. The
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most important amino acid found in GT is theanine. Theanine as an analogue of L-glutamic acid evokes many
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pharmacological and therapeutic effects [5]. Historically, the scientific evaluation of GT was initiated in 1950s-

1960s, when the main compounds of GT were discovered [6-13]. It has currently been demonstrated that GT

and its main constituents have considerable effects on treatment of cancer, obesity, diabetes [14], arthritis and

cardiovascular diseases, by functioning as anti-viral and anti-carcinogenic [4] and neuroprotective [15, 16]

properties.
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In this review, we will give a brief summary of some special natural or chemical toxins, followed by a

description of the antidotal effects of GT and its main components on them by mechanistically view to introduce

a valuable traditional antidote against wide range of toxins.

1. Methods

A comprehensive literature review was performed using relevant keywords, including Camellia

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sinensis, green tea, catechin, epicatechin, epicatechin gallate, gallocatechin, epigallocatechin, epigallocatechin

gallate, natural toxins, chemical toxins, neurotoxins, cardiotoxins, hepatotoxins and nephrotoxins in the

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following databases: Scopus, PubMed and Web of science. No time limitation was considered in this review.

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Both in vitro and in vivo studies were included to this experiment. Non-English language articles, congress

abstracts, as well as studies on black tea or the other plants with similar secondary metabolites were considered

ineligible for inclusion. The antidotal effects of GT and the respective compounds were categorized into two

main heading: natural and chemical toxins.

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3. Natural toxins
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Evidences have shown that GT and the respective secondary metabolites exhibit antidotal effects

against several natural toxins, including some type of mycotoxins, snake venoms and bacterial toxins. These
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protective impacts were attributed to the effect of GT and related compounds, as anti-oxidative, and anti-
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inflammatory properties, on the toxin metabolism, as well as neutralizing PLA2, proteases, hyaluronidase and l-

amino acid oxidase enzymes (Figure 2).

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3.1. Mycotoxins
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3.1.1. Aflatoxin
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Aflatoxins, recognized as hazardous food contaminants, are mainly produced by Aspergilus flavus and

Aspergillus parasiticus. Among them, the most carcinogenic type is aflatoxin B1 (AFB) behaving as

hepatotoxic and genotoxic agents too [17]. GT leaf extract inhibits producing aflatoxin by A. parasiticus,

however it has low inhibitory influence against A. flavus [18]. In addition, several investigations demonstrated

the protective effect of GT polyphenols (GTP) against AFB. In young male Fischer rats, GT extract

administration (GTE; 0.5%, in drinking water) improved AFB (1 mg/kg, i.p.) metabolism by enhancing

formation of non-toxic AFB metabolites and inhibited the AFB ([3H]AFB1, 0.4 mg/kg, i.p.) binding to DNA
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[19]. Furthermore, it has been determined that AFB (10 mg/kg, i.p.) could induce chromosomal aberrations in

rats bone marrow. In this study, Ito et al. showed that administration of GTE (0.1- 2 g/kg gavage) could

suppress side-effects of AFB i.p. [20].

3.1.2. Patulin

Patulin (PAT) is a mycotoxin produced by a variety of molds, in particular Penicillium, Aspergillus and

Byssochlamys [21, 22]. PAT is found in fruits and vegetables, most commonly in rotting apples and apple

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products [23]. PAT has been determined as a toxic, mutagenic, carcinogenic, and teratogenic agent in animals

[21]. In this regard, World Health Organization (WHO), US Food and Drug Administration (FDA) and also

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European Union have revealed the maximum permitted levels of PAT in foods and juices [22, 24]. Study in

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mouse models showed that GTPs administration (25, 50 and 100 mg/kg, i.p.) possess protective effects against

PAT (1 mg/kg,i.p.) induced hepatotoxicity, via reduction of several hepatic injury markers, including alanine

aminotransferase (ALT), aspartate aminotransferase (AST), reactive oxygen species (ROS) and thiobarbituric

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acid reactive substances (TBARS). GTPs could also increase hepatic antioxidant activities, such as glutathione
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(GSH), superoxide dismutase (SOD) and catalase (CAT) in the respective mice. Moreover, it has been shown

that GTPs inhibited PAT-induced bone marrow damage, including the formation of micronucleus and
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chromosomal aberration, as a marker of PAT induced genotoxicity effects [25].

3.1.3. Deoxynivalenol
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Deoxynivalenol (DON), is a trichothecene mycotoxin and secondary metabolite obtained from

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Fusarium, Myrothecium, Cephalosporium, Verticimonosporium and Stachybotrys species [26]. It is found

predominantly in grains. As a toxin, it induces ribotoxic stress response and mainly affects actively growing
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cells such as those of the immune system and the gastrointestinal tract [27]. A direct relationship among the

incidence of esophageal and gastric cancers with consumption of DON contaminated grains has been
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established by Marasas et al. in 1979 [28]. It has been demonstrated that EGCG pre-treatment has
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cytoprotective effects on HT-29 cells by alleviating DON-induced toxicity. The incubation of HT-29 cells with

EGCG (20 M), before adding DON (250 and 500 M), increased the cell viability, improved the activity of

oxidative stress, nuclear factor-kB (NF-B), cyclooxygenase-2 (COX-2) and caspase-3, while it protected

against apoptosis in comparison with DON treatment alone [27]. Furthermore, Sugiyama et al. (2011)

demonstrated that protective effect of EGCG (10 and 20 M) against DON (2000 ng/ml) and HT-2 toxin (200

ng/ml), as another trichothecene mycotoxin, induced cytotoxicity in mouse macrophages (RAW264). This

protective effect was attributed to caspase-3/7 activity suppression [29].

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3.1.4. Three-nitropropionic acid

Three-nitropropionic acid (3-NPA) is a mycotoxin potentially inhibiting mitochondrial respiratory

complex II. It has been reported that eating moldy sugarcane contaminated by 3-NPA is fatal [30]. In animals,

this agent causes neurotoxicity and Huntingtons like symptoms due to aberration of oxidative stress and nitric

oxide mechanisms [31]. Kumar et al. (2009) showed that EGCG (10, 20 and 40 mg/kg, by gavage) pre-

treatment improved behavioral alterations, oxidative and mitochondrial damages, as well as striatal injury in 3-

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NP (10 mg/kg, i.p.)-treated rats [32]. Furthermore, they proved the protective effects of EGCG pre-treatment

against 3-NPA induced cognitive dysfunction in rats [33]. According to their studies, EGCG protective effects

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might be due to nitric oxide synthase (NOS) inhibition, considering that these protective effects are reversed and

potentiated by L-arginine (50 mg/kg, i.p.) and L-NG-Nitroarginine methyl ester (L-NAME; 10 mg/kg, i.p.),

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respectively [32, 33].

3.1.5. Ochratoxin A

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Ochratoxin A (OTA), as a nephrotoxic and carcinogenic mycotoxin, is produced by several Aspergillus
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and Penicillium species. It is one of the most-abundant food-contaminating mycotoxins [34]. It has been shown

that catechin has inhibitory effects on the OTA production and growth of some Aspergillus species [35]. Costa
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et al. showed the protective effects of EGCG and ECG against OTA-induced cytotoxicity in a pig kidney cell

line, LLC-PK1. In this study pre-treatment with catechin increased cell viability, decreased ROS production and
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prevented OTA-induced DNA fragmentation with respect to OTA alone [36]. However, former studies on liver
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cells, HepG2, had shown that EGCG [37, 38] or epicatechin [38] had no protective effects against OTA-induced

toxicity, by pre-treatment with catechin.

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3.2. Snake venoms

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Investigations signify that Bothrops venom, whereby phospholipases A2 (PLA2s) is the main
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component, could cause prominent myonecrosis, hemorrhage, and edema [39]. In addition, the protective effects

of C. sinensis extract against irreversible neuromuscular blockade of Crotalus durissus terrificus venom was

reported in the mouse phrenic nerve diaphragm preparation. Histological data obtained from diaphragm muscle

confirmed the protective effects of C. sinensis extract against the myotoxic activity of the venom [40].

Moreover, the protective effects of C. sinensis methanolic extract against Naja naja kaouthia Lesson (Elapidae)

and Calloselasma rhodostoma Kuhl (Viperidae) venoms have been shown. In vitro, C. sinensis methanolic

extract neutralized PLA2, proteases, hyaluronidase and l-amino acid oxidase in both venoms. Besides, in vivo
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pre-treatment with this extract diminished the hemorrhagic and the dermonecrotic activities of the venoms.

These protective effects of C. sinensis were attributed to chelation between the phenolic contents of the extract

and venom proteins [41]. In a study on the egg yolk and 4-nitro-3-(octanoyloxy)benzoic acid, as PLA2

substrates, it was determined that EGCG inhibits the enzymatic activity of PLA2. Besides, EGCG inhibited

miotoxicity of PLA2 in murine myotubes which is measured as lactic dehydrogenase activity and obtained from

C2C12 skeletal muscle myoblast. These protective effects were attributed to EGCG physicochemical properties;

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where it has a great capacity to make hydrogen bond interactions and provide a high affinity for PLA2 to form a

stable complex [42].

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However, Kuppusamy and Das previously showed that catechin had no effect on the hyaluronidase

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activity of five different venoms (Apis mellifera, Scorpio maurus palmatus, Crotalus adamenteus, Crotalus

atrox, Naja naja sputatrix). In this study, hyaluronidase activity was evaluated by spectrophotometer in the pre-

incubated mixture of venom solutions with catechin and hyaluronic acid [43].

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3.3. Bacterial toxins

3.3.1. Botulinum
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Clostridium botulinum is an anaerobic, spore-forming bacterium with the ability to produce the botulinum which

is a potent neurotoxin [44]. It was shown that catechins have the ability to inhibit the vegetative growth of C.
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botulinum and decrease the number of C. botulinum spores. Using fluorescence microscopy, on the C. butyricum
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spores, damage to the spore membrane was revealed after 8 weeks of incubation with GT derivatives. It has

been proposed that spore membrane of spore-forming bacterial pathogens could be sensitive to catechins and
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damage their membrane [45].

3.3.2. Lipopolysaccharide
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Lipopolysaccharide (LPS) is the major player in sepsis, a systemic inflammatory response syndrome
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with severe infection and inflammation [46]. Based on the current study performed by Tominari et al., EGCG

could suppress LPS-induced inflammatory bone resorption. Briefly, in both organ cultures of mouse mandibular

alveolar bone and calvariae, bone-resorption activity of LPS (1 g/ml) was decreased by using EGCG (30, 60

and 90 M). In this study, LPS induced expression of COX-2, microsomal prostaglandin E synthase-1 and 2 as

well as receptor activator of nuclear factor kappa-B ligand, while production of PGE2 in mouse primary

osteoblasts were suppressed by EGCG (30 M) treatment. In addition, EGCG administration (0.5 mg/mouse)

into the lower gingiva of LPS-treated mice (25 g/mouse) improved alveolar bone mass [47]. Another study
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showed that EGCG (25 and 100 mg/kg) application could diminish LPS (10 g)-induced mastitis in rats, by

modulating oxidative stress and inflammatory responses. EGCG pre-treatment, during gestation, suppressed the

LPS-induced mammary expression of mitogen-activated protein kinases (MAPKs), nuclear factor B-p65

(NFB-p65) and hypoxia-inducible factor-1 (HIF-1) [48].

Several studies have attributed anti-inflammatory effect of EGCG to Toll-like receptor 4 (TLR-4)

inhibition. It has been revealed that EGCG could suppress LPS-induced TLR-4 signaling and inflammation via

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67-kDa laminin receptor (67LR) [49-52] and Toll interacting protein [51, 53]. Suppressing high mobility group

box 1 protein [54], blocking TLR-4-NFB signaling pathway [55], attenuating activation and phosphorylation of

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extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), P38 [56], AkT [57, 58], in addition to reducing

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TNF- and NO inflammatory mediators [59] are the other proposed mechanisms of EGCG against LPS-induced

inflammation, in several literatures. Besides, it has been shown that GT pro-anthocyanidins might evoke anti-

inflammatory properties through blocking MAPK-mediated COX-2 expression [60]. Some of these studies are

summarized in the table 1.

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3.3.3. Microcystin-LR

Microcystin-LR (MC-LR) is a toxin produced by cyanobacteria [61]. Hepatotoxicity of MC-LR has

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been shown in various studies [62]. As a case, investigations showed that repetitive exposure to MCLR could

lead to hepatotoxicity. Briefly, MCLR (10 g/kg/day, i.p.) was given to healthy Kunming male mice, for 12
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days, while GTP (50, 100 and 200mg/kg/day, orally) prior to MCLR intoxication was administrated for 18 days.
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Findings showed that MCLR increased serum and liver lipid peroxidation, hepatocellular apoptosis as well as

pathological changes. GTP pre-treatment ameliorated MCLR induced oxidative stress and protected
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biochemical markers and pathological changes, induced by MCLR, dose dependently [62].
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3.4. Other natural toxins

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3.4.1. D-Galactosamine

D-Galactosamine (D-GalN) is a natural hepatotoxic agent. It could induce liver damage, similar to that

of acute viral hepatitis [63]. Investigations demonstrated the hepatoprotective effect of GT against D-GalN

induced toxicity. Thus, it has been shown that catechin treatment (50 and 100 mg/kg, oral administration for one

week) significantly increased the liver enzyme activity and decreased antioxidant enzyme activity induced by

injection of D-GalN (400 mg/kg, i.p.). It was also found that pre-treatment with catechin significantly protected
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against disruption of mitochondrial membrane potential, up-regulation of liver p53 as well as Bax and down-

regulation of Bcl2 mRNA levels in D-GalN intoxicated rats [64].

3.4.2. Khat

Khat (Catha edulis Forsk) is a shrub belongs to the Celastraceae family. It is mainly cultivated in

Yemen and East African Countries. Approximately, 20 million people in these countries chew daily khats

young shoots and leaves [65]. Khat consumption is considered to be addictive due to the presence of the

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phenylpropylamino alkaloids, while these alkaloids are responsible for the continued chewing behavior [66].

The adverse effects of khat on different aspects of health have been reported. Studies showed that GT

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administration has strong hepatoprotective effects against khat induced hepatotoxicity in rats, by inhibiting

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oxidative stress. It has been revealed that GT significantly neutralized the alterations in liver function tests,

decreased lipid peroxidation and restored antioxidants status near to the normal levels [67].

4. Chemical induced toxicity

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GT and its main compounds have antidotal and protective effects against a wide range of chemical

toxins. In this section, we discuss about antidotal effects of GT and its secondary metabolites against metals,
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fluoride, pesticides, cardiotoxic agents (doxorubicin, idarubicin, daunorubicin isoproterenol, cabergoline,

amiodarone), neurotoxic agents (glutamate, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 6-hydroxydopamine,

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amyloid , acrylamide, bupivacaine, kanamycin, oxaliplatin, advanced glycation end products, quinolinic acid),
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hepatotoxic agents (acetaminophen, doxorubicin, halothane, azathioprine, ethanol, carbon tetrachloride,

Vinylidene chloride, nitropropane, 1,4-naphthoquinone, dextran sulfate sodium, formaldehyde, 4-

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Nitroquinoline-1-oxide) and nephrotoxic agents (gentamicin, cisplatin, cyclosporine, tacrolimus). Besides, in

this section some important protective mechanisms are discussed (Figure 3).
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4.1. Metals

4.1.1. Aluminum

Aluminum (Al) is one of the most abundant metals on the earths crust [68]. Aluminum, as a toxin,

could cause renal osteodystrophy, dialysis dementia and Alzheimers disease [69]. It was demonstrated by

Jelenkovic et al. (2014) that GT leaf extract has protective effects against aluminum chloride (3.7104 g/kg,

injected into the left brain hemisphere cornu ammonis region 1) neurotoxicity in rats. Pre-treatment with GT

improved cognitive impairments and brain cytochrome c oxidase, acetyl cholinesterase, SOD activities and total
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glutathione content [70]. In addition, it recovered mitochondrial and cholinergic synaptic functions [70], while

anti-oxidative effect [70, 71] has been discussed as the protective mechanism of GTE on aluminum toxicity.

4.1.2. Arsenic

Arsenic, a metalloid element, is categorized as a class I carcinogen that causes acute and chronic

toxicity [72]. Sarkozi et al. explained the protective effect of GT against arsenic neurotoxicity in Wistar rats.

Arsenic (NaAsO2, 10 mg/kg, by gavage) increased lipid peroxidation in cortex, increased latency of cortical

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evoked potentials and decreased tail nerve conduction velocity. Treatment of animal models with GT infusion

(20.5 g in 500 ml drinking water) improved neurotoxic effects [73].

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4.1.3. Cadmium

Cadmium (Cd2+), as a heavy metal, is extremely hepatotoxic and nephrotoxic, commonly used in

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industrial products, cigarettes and even in foods [74, 75]. Itai-itai disease, a form of Cd2+-induced renal

osteomalacia, is a well-known abnormality that was identified for the first time in Japan [76]. Toxic effects of

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Cd2+ on the central nervous system has been reported in several studies [77]. In addition, the protective effects
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of EGCG against Cd2+ induced hepatotoxicity has been shown by Haouem et al. on the normal human liver cell

line, HL-7702. They showed that EGCG treatment (20 M) improved cell viability and apoptosis, after
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exposure to Cd2+ (60 M). Besides, EGCG counteracted generation of intracellular ROS and malondialdehyde

(MDA) which further prevented mitochondrial membrane potential disruption and blocked caspase-3 activity
D

[74]. It has also been demonstrated that EGCG could protect against Cd2+ induced toxicity in mitochondrial-
TE

enriched fractions from rat brain. Thus, co-incubation of EGCG (100 M) with Cd2+ (200 M) counteracted the

toxic effects of this heavy metal on the mitochondrial dysfunction and lipid peroxidation. These protective
EP

effects were attributed to anti-oxidant and chelating effects of EGCG [78]. However, Ozdemir et al.

demonstrated that catechin (0.2 g/L, in drinking water) had no effect against Cd2+ (120 mg/L, in drinking water)
C

induced lipid peroxidation, toxicity and Cd2+ accumulation, in Wistar rat testis tissue [79].
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4.1.4. Copper

Copper is one of the first engineered nanoparticles used in a variety of industrial applications, such as

facial spray, lubricants additive, metallic coating, and inks [80]. Although, copper nanoparticles (CNPs) could

also induce toxic effects, including hepatotoxicity, due to their small size and high reactivity [81]. Studies

showed that rats treated with CNPs significantly elevated liver enzymes. They also demonstrated alteration in

antioxidant defense system and severe pathological damages. Moreover, a significant increase in DNA

fragmentation, marked DNA laddering, as well as up-regulation of caspase3 and Bax protein levels were
 17
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observed. Curiously, it has been determined that GTE could significantly alleviate the hepatotoxicity and

apoptosis induced by CNPs [82].

4.1.5. Mercuric

The injection of mercury (II) chloride (HgCl2) increased lactate dehydrogenase (LDH), aspartate

aminotransferase (ALT), apoptosis, reactive oxygen species (ROS), glutathione (GSH) and malondialdehyde

(MDA) levels. Pathological and ultra-structural abnormalities were also observed following HgCl2 injection. It

PT
has been demonstrated that glutathione peroxidase (GSPx) and SOD activities were decreased by HgCl2

injection. Schisandrin B and GTPs, two naturally antioxidants, could protect liver against Hg induced

RI
hepatotoxicity, by increasing the antioxidant defense system [83].

SC
4.1.6. Lead

Lead (Pb) intoxication is a serious occupational disease in some industries. Ingestion or inhalation of

lead and the respective compounds could cause neurotoxicity and brain disorders [84]. It has been reported that

U
GT consumption could reduce the adverse effects of environmental Pb and cadmium (Cd) pollutions. In Wistar
AN
rats exposed to Pb (50 mg/kg) and Cd (7 mg/kg), GT reduced accumulation of these heavy metals in vital tissues

and increased activity of SOD, catalase (CAT), as well as glutathione peroxidase (GPx) [85]. Chen et al.
M

revealed that GT catechins (especially galloylated catechins) minimized toxic effects of Pb in the HepG2 cells

by promoting disruptive effects on the cell membrane fluidity. A significant increase in the cell viability and
D

decrease in lipid peroxidation levels were observed in the tea catechin supplemented groups, while HepG2 cells
TE

were exposed to Pb [86]. It has also been shown that co-exposure of Pb (100 M) with catechins (50 and 100

M) increased cell viability, intracellular Ca2+ level, ROS formation and improved mitochondrial membrane
EP

potential [87]. Similar to this study, the protective effect of EGCG on cell viability in Pb-intoxicated human

neuroblastoma cells was reported [88]. These findings were in agreement with Khalaf et al. reports, indicating
C

protective effect of GT against neurotoxicity induced by Pb (100 mg/kg, by gavage) in rat. Co-treatment with
AC

GT (5 g/L, drinking water) very significantly counteracted toxic effects of Pb on loss of body weight and high

DNA fragmentation. Besides, GT co-treatment with Pb increased the concentration of reduced glutathione and

SOD activity in brain tissues [89]. In the other study, protective effects of GT against side-effects induced by Pb

were investigated. Pb (100 mg/kg, oral administration for one month) induced a significant increase in kidney

lipid peroxidation as well as decrease in kidney antioxidant enzymes CAT, SOD and GPx which were

accompanied with pathological changes. However, co-treatment with GTE (5 g/L in drinking water for one

month) alleviated these adverse effects [89].

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4.1.7. The other heavy metals

In addition, several investigations demonstrated protective effects of GT polyphenols on reduction of

oxidative responses, induced by nickel and cisplatin in rats [90]. It has also been determined that GT

polyphenols produces less toxic form of chromium (trivalent chromium (Cr(III)) ion from hexavalent chromium

(Cr (VI)) ion) in aqueous solution [91]. Besides, it has been reported that toxicity induced by vanadium could be

prohibited using GTEs, due to their antioxidant properties [92] and chelating activity [92, 93]. It was proposed

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that GT polyphenols, by forming insoluble complexes of vanadium, could increase its exertion in feces [93].

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4.2. Fluoride

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It has been demonstrated that chronic exposure to fluoride (F) could evoke myocardial damages,

cardiomyopathy and cardiac arrhythmias [94]. Nabavi et al. showed the protective effects of EGCG against F

(25 mg/kg, by gavage for 4 weeks) induced cardiotoxicity. EGCG (40 mg/kg, 4 weeks) improved toxic effects

U
of F, by reducing the level of cardiac injury markers, lipid peroxidation products and increasing antioxidant
AN
status as well as mitochondrial function. It could also regulate expressions of apoptotic, and inflammatory

markers in the heart, due to antioxidant actions and free radical scavenging of EGCG [95]. These protective
M

mechanisms of EGCG in F-induced cardiotoxicity have been proved recently [96]. High level intake of NaF is

believed to cause structural changes, altered activities of enzymes in the liver and lipid metabolism changes
D

[97]. Administration of EGCG (40 mg/kg) significantly improved the altered biochemical indices, including
TE

DNA damage and pathological changes which were caused by NaF intoxication of rats liver [98].
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4.3. Pesticides

Pesticides are substances generally used for killing or repelling pests or related reproductions. The term
C

of pesticide is often accompanied with insecticides, fungicides, rodenticides, pediculocides, and biocides.
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Common application of pesticides in different situation remarkably expose human health to these toxic products

[99].

4.3.1. Chlorpyrifos

Chlorpyrifos is a broadly used organophosphorus insecticide around the world, causing toxic effects on

different tissues, like liver [100]. It has been reported that catechin [101] and GTE [102] has protective effect

against chlorpyrifos induced hepatotoxicity in rat, by improving histopathological changes, restoring antioxidant

enzyme activities and biochemical markers as well as alleviating lipid peroxidation [101, 102]. Besides, GTE
 19
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could prohibit reproductive toxicity [103], cardiotoxicity [104] and liver toxicity caused by exposure to

chlorpyrifos [105], possibly due to catechin anti-oxidant effects [101].

4.3.2. Cyromazine

Cyromazine, is an insects growth regulator which acts by inhibiting the moulting processes [106]. The

protective effect of GT aqueous extract (1.5% w/v/day, drinking water for 28 days) against hepatotoxicity and

oxidative damage induced by cyromazine (169.33 mg/kg/day. via gavage, for 28 days) and its combination with

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chlorpyrifos (6.75 mg/kg/day, via gavage, for 28 days) in male rats was investigated. Administration of these

insecticides significantly caused loss of body weight, serum albumin, as well as decrease in hepatic LDH, GPx

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and GSH. They also increased liver weight, serum transaminases (AST and ALT), ALP, total protein, lipid

SC
peroxidation, LDH, hepatic SOD, CAT and hepatic protein carbonyl content. Liver histopathological

examination showed that GTE ameliorated cyromazine induced degeneration and necrosis of the hepatocytes.

GTE antioxidant properties attenuated and restored damages induced by insecticide exposure [102].

4.3.3. Diazinon
U
AN
Diazinon intoxication, an organophosphate insecticide, is generally due to inhibition of

acetylcholinesterase activity and oxidative stress [107]. Previously we have shown cardiotoxic effects of DZN is
M

associated with increase in oxidative stress and apoptosis in cardiac [108] and aorta tissues [109] which was

accompanied with decrease in systolic blood pressure and increase in the heart rate [110]. Besides, DZN has
D

ability to induce neurotoxicity [111], hepatotoxicity [112] and genotoxicity [113]. The protective effect of GT
TE

on diazinon intoxication was demonstrated by Al-Attar et al. in 2013 [114]. It has been shown that diazinon in

mouse sublethal concentration (6.5 mg/kg, i.p. for seven weeks) increased ALT, AST, gamma glutamyl
EP

transferase, alkaline phosphatase, creatine kinase, creatinine, glucose, triglycerides, and cholesterol; while it

decreased serum total protein concentration. Investigations showed that treatment with GT (400 mg/kg, orally, 4
C

hours before diazinon injection) could prohibit side-effects caused by diazinon induction [114].
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4.3.4. Deltamethrin

Deltamethrin is the other widely used insecticide around the world. Although it was initially introduced

as a safe product for human, current investigation showed that is neurotoxic [115]. It has been shown that co-

treatment GTE (25 mg/kg, by gavage) with deltamethrin (0.6 mg/kg, by gavage) decreased oxidative status

(MDA content, nitric oxide concentration) and DNA fragmentation. It has also suppressed the expression of p53

and COX-2 genes in the brain tissue [116].

4.3.5. Dieldrin
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Dieldrin, an organochlorine insecticide, has neurotoxic properties by blocking GABA receptors [117].

The protective effect of L-theanine against dieldrin toxicity has been proved by Cho et al. [118]. They showed

that L-theanine diminished the effects of dieldrin on DNA fragmentation, heme oxygenase 1 up-regulation and

apoptosis. Besides, L-theanine blocked the effects of dieldrin and improved p-ERK, brain-derived neurotrophic

factor and glial cell line-derived neurotrophic factor content in SH-SY5Y cells induced by dieldrin [118].

4.3.6. Malathion

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Malathion, as an organophosphorus compound, is widely used for agricultural crops to control pests

and public health programs. It has been reported that malathion reduced liver GSH, GSH-PX and SOD levels

RI
and increased MDA and histopathological damages. In contrast, modulatory effects of GT and vitamin C against

SC
malathion liver toxicity have been investigated. Findings showed that co-administration of vitamin C and GT

(36 mg/kg, i.p.) significantly normalized, some hematological and biochemical parameters altered by malathion

(50 mg/kg, i.p., four weeks) [119].

4.3.7. Methyl parathion

U
AN
Methyl parathion (mPT) is an extremely toxic organophosphorus pesticide [120]. In addition to the

acetyl cholinesterase inhibition, it can damage tissues through oxidative stress. Argentin et al. indicated that
M

EGCG (10, 25 and 50 M) reduced cytotoxicity induced by mPT (10, 50 and 10 g/ml) in human gingival

fibroblasts through suppression oxidative stress, cytotoxicity, and genotoxicity [121]. EGCG also decreased
D

dichlorodiphenyltrichloroethane (DDT), a pesticide, induced cell toxicity. In this study, pretreatment with
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EGCG (1, 3 and 10 M) increased cell viability in dopaminergic neuroblastoma cells, SHSY-5Y, which were

exposed to DDT (100 M) treated alone [122].

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4.3.8. Paraquat

Paraquat (PQ), functioning as an herbicide, induces neurotoxicity through oxidative stress [123]. In
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Drosophila melanogaster, it has been revealed that feeding with epicatechin, epigallocatechin, and
AC

epigallocatechin gallate, after exposing to paraquat, improved survival rate and locomotor dysfunction. These

neuroprotective effects were attributed to ROS scavenger activity and antioxidant capacity of GTPs [124]. It has

also been demonstrated that EGCG could modify features of Parkinsons disease in PQ treated cell line that

retains the properties of dopaminergic neurons, PC12 cells, via inhibiting caspase-3 activity, modulating

mitochondrial function and down-regulating the expression of a pro-apoptotic protein, Smac, in cytosol. Pre-

treatment with EGCG (1, 5 and 10 M) increased cell viability and attenuated apoptosis, caused by PQ

induction (800 M) [125]. In vitro study on Chinese hamster lung cells (CHL) revealed the other protective
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mechanism of GTPs against PQ intoxication. It was shown that GTPs (EGCG and catechin) suppressed PQ

induced genotoxicity effect by inhibiting sister chromatid exchange (a mutagen and carcinogen marker) and

ROS formation [126]. In the other study on PQ-induced microsomal MDA productions in rat liver microsome

system containing 40 M FeSO4, it was showed that the EGCG inhibits MDA production while adding

excessive amount of FeSO4 counteracts with EGCG protective effects. Radical scavenging activity of EGCG

concomitant with iron-chelating activity was considered as a protective mechanism of EGCG against PQ

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intoxication [127]. Furthermore, El-Sayed et al. showed an antagonist effect for GT, due to antioxidant

properties, against PQ-induced lung injury. It was shown that co-treatment with GTE (1 mg/kg, orally)

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prohibited the PQ-induced lung histopathological feature and attenuated the effects of this herbicide on lung

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myeloperoxidase, SOD and lactate dehydrogenase (LDH) activities as well as TBARs, GSH and protein thiols

content [128]. It has been indicated that suppressing oxidative stress and endothelin-1 (ET-1) expression were

part of mechanism(s), whereby GTE roles against PQ-induced pulmonary fibrosis [129]. In this study, Kim et

U
al. demonstrated that co-treatment of PQ (0.3 mg/kg, instilled into the right lung) intoxicated rats with GTE (1%
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mixed with feed) attenuated lung fibrosis, and decreased ET-1, Prepro-ET-1 mRNA expressions and MDA in

lung [129]. These findings were consistent with previously performed study, implicating protective effects of
M

EGCG and ECG on PQ-induced toxicity in rat [130].

4.3.9. Rotenone
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Rotenone, an organic pesticide, is naturally present in the Derris, Lonchocarpus, Tephrosia and
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Mundulea plants [131]. Cho et al. (2008) showed that L-theanine (an amino acid in GT) attenuated the toxic

effects of rotenone in SH-SY5Y cells. L-theanine (500 mM) reversed the effects of rotenone on DNA
EP

fragmentation, heme oxygenase 1 up-regulation and apoptosis. Besides, pre-treatment with L-theanine increased

p-ERK, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor content in SH-SY5Y
C

cells treated with rotenone [118]. However, it has been shown that EGCG at higher concentration has no
AC

protective effect and promotes neurotoxicity of the rotenone by enhancing apoptosis and intracellular production

of superoxide [132].

4.4. Protective effects of GT and respective components against cardiotoxic xenobiotic

4.4.1. Anthracyclines

Doxorubicin (Dox) is a considerable anthracycline antitumor antibiotic, threatening life by releasing

ROS and causing cardiotoxicity [133]. It enhances lipid peroxidation and decreases biosynthesis of highly
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unsaturated fatty acids [134] leading to dose-limited treatment [133]. Many studies revealed the protective

effects of GTPs in mitigation of cardiotoxicity in the treated cells with Dox (table 2). These documents have

attributed the protective effects of GTPs to their anti-oxidant properties [135-144]. Chelating properties [142],

modulating apoptosis pathways [135, 138], scavenging ROS [145], and modifying cardiomyocyte fatty acid

pattern [146] are the other engaged cardioprotective mechanism of GTPs. Besides, it has been indicated that the

concomitant of GTPs and DOX applications increase therapeutic efficacy of DOX [147]. Furthermore,

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cardioprotective effects of GT in relation to theanine, an abundant amino acid in GT, in Dox-induced

cardiotoxicity have been explained [148].

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It has been demonstrated that catechin (i.p.) can prohibit cardiac cells against toxicity induced by

SC
idarubicin, as an anthracycline antitumor antibiotic. During 5 weeks, catechin (200 mg/kg/week, i.p.) was

administrated 30 minutes after idarubicin injection (5 mg/kg/week, i.v.). A significant reduction in the heart

mitochondrial swelling and vacuolization were observed in catechin treated rats, while heart muscle

U
antioxidants, including CAT, SOD, and GPx, were increased [149]. In addition, protective effects of EGCG
AN
peracetylated derivative against daunorubicin (another anthracycline antitumor antibiotic)-induced

cardiotoxicity were attributed to enhancing SOD activities and anti-lipid peroxidation of EGCG [150].
M

4.4.2. Isoproterenol

Previously, we showed isoproterenol (ISO) induced myocardial infarction in rats is accompanied with
D

increase in LDH and creatine kinase-MB activities in serum with lipid peroxidation and necrosis in the heart
TE

tissue [151]. Investigations showed that EGCG, with regards to free radical scavenging action and anti-oxidant

properties, prohibits damages caused by ISO exposure to heart [152, 153]. In addition, it has been shown that
EP

EGCG could effectively stabilize membrane against ISO induction [154]. This study demonstrated that heart

mitochondrial level of cholesterol, triglyceride, free fatty acids, Ca2+ and lipid peroxidation content were
C

increased in ISO group (100 mg/kg/day, subcutaneously administrated for two consecutive days) accompanying
AC

with decrease in the heart mitochondrial content of phospholipids, antioxidants, tricarboxylic acid cycle

enzymes as well as ATP level. On the other hand, pre-treatment with EGCG (30 mg/kg, by gavage, for 21 days)

mitigated ISO toxic effects on the heart mitochondria [152, 153]. Besides, pre-treatment with EGCG (10, 20 and

30 mg/kg, by gavage, for 21 days) decreased activities of Ca2+ and Mg2+ ATPases in ISO-induced myocardial

infarction in rats [154].

4.4.3. The other cardiotoxic agents

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The protective effects of GT against cabergoline [155] and amiodarone [156] induced cardiotoxicity

have been mentioned.

4.5. Protective effects of GT and respective components against neurotoxic agents

4.5.1. Glutamate

Glutamate induced neurotoxicity is associated with the production of ROS in the neurons [157]. Recent

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studies performed by Cong et al. showed that GTPs could ameliorate neurotoxicity of glutamate (40 M) in

primary cultured cortical neurons. Since pre-exposure to GTPs (10 M) increased cell viability, SOD activity

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and restored dysfunction of mitochondrial pro- or anti-apoptotic proteins (Bax, caspase-3 and Bcl-2), in

SC
comparison with cells treated only with glutamate, these protective effect could be attributed to anti-oxidative

and anti-apoptotic mechanisms induced by GTPs [158]. In this regard, several investigations revealed the

protective effects of EGCG (1100 M) and epicatechin (100 M) against toxicity induced by glutamate

U
exposure (5 mM and 100 g/ml, respectively) in HT22 cells, mouse hippocampal cell line, due to their
AN
antioxidant properties [159-161]. In the other study, it has been shown that L-theanine protected cells against

glutamate-induced excitotoxicity by inhibiting N-methyl-D-aspartate (NMDA) receptor and related pathways

M

[162]. However, Mazzio et al. showed no significant protection against glutamate-induced toxicity in PC12 cells

using catechin, EGCG and GT treatments [163].

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4.5.2. N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

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MPTP, a chemical impurity found in heroin, contributes to neuropathological changes and clinical

features similar to Parkinsons disease. 1-methyl-4-phenylpyridinium (MPP) is a metabolite of MPTP in brain

EP

that evokes dopaminergic cells injury [164]. It has been revealed that EGCG prevents MPTP-induced toxicity in

mice. Investigations revealed that EGCG (25 mg/kg, by gavage) could reverse the effects of MPTP on the
C

tyrosine hydroxylase activity, dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid content of the
AC

mice striatum, by inhibition of nNOS in the substantia nigra [165]. In addition, neuroprotective effects of

catechin against toxicity of MPTP were attributed to the suppression of c-Jun N-terminal kinases (JNK) and

glycogen synthase kinase 3 (GSK-3) signaling cascades [166], and inhibition of dopamine transporters that

block MPP uptake and protect dopaminergic neurons against MPP-induced injury [167]. Similarly, Ruan et al.

discussed that the protective effects of catechin against MPP induced neurotoxicity was performed through anti-

oxidative stress and inhibition of the JNK/c-Jun signaling pathway [168].

4.5.3. 6-Hydroxydopamine
 24
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Investigations reported that 6-hydroxydopamine (6-OHDA) induced neurotoxicity, likely due to excess

iron influx and production of free radicals via Fenton reaction that evokes neurological disorders including

Parkinsons disease [169]. It has been shown that pre-treatment with EGCG (100 M), by regulating iron related

proteins (divalent metal transporter-1, iron exporter ferroportin 1 and hepcidin), has a protective effect against

neurotoxicity caused by 6-HODA (25 M) treatment in N27 cells, immortalized rat mesencephalic

dopaminergic neuronal cell line [170]. Furthermore, it has been revealed that EGCG has protective effects

PT
against 6-HODA, but not methyl-4-phenylpyridinium iodide (MPP) induced neurotoxicity. MPP causes

neurotoxicity though p53-dependent apoptosis pathway, whereas 6-OHDA produces ROS [171]. This study also

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implicated that scavenging free radicals could be proposed as the other neuroprotective mechanism of EGCG

SC
activity. Moreover, Teixeira et al. presented that catechin (10 and 30 mg/kg, i.p., 14 days) improved working

memory, increased tyrosine hydroxylase in both mesencephalic and striatal tissues. These protecting effects of

catechin could be attributed to its antioxidant action [172]. In the other study, it was revealed that catechin could

U
protect against neurotoxicity caused by 6-OHDA induction, through activating anti-apoptotic pathways. Pre-
AN
treatment with catechin (100 M) reduced the 6-OHDA (175 M)-induced apoptosis in mouse PC12 cells.

Beside, intracellular ROS accumulation and caspase-8 activity were significantly prohibited by pre-treatment
M

with catechin in 6-OHDA-induced toxicity in this model [173].

4.5.4. Amyloid
D

Amyloid (A) aggregation in the brain creates extracellular deposits, known as senile plaques, which
TE

are a principal pathological feature of Alzheimers disease [174]. It has been revealed that EGCG@Se (EGCG

on the surface of selenium nanoparticles) and Tet-1-EGCG@Se (EGCG-stabilized selenium nanoparticles

EP

coated with Tet-1 peptide) nanoparticles can evoke neuroprotective effects by inhibiting A fibrillation and

accumulation [175]. Chung Wei et al. recently showed that anti-oxidative effects of EGCG could protect EOC
C

13.31 cells, mouse immortalized microglia cells, from A-induced microglial inflammation and neurotoxicity
AC

[176]. It has been implicated that neuroprotective effects of GT and its derivatives against A are attributed to

their anti-oxidative function [177-183], inhibition of the NMDA receptors [162] and glycogen synthase kinase 3

beta (GSK3) [184], activation of 7 nicotinic acetylcholine receptors (nAChR) [185], protein kinase C (PKC)

[186, 187], phosphoinositide 3-kinase (PI3K)/AKT signaling pathway [185, 188] as well as suppression of c-

Abl/FE65 nuclear translocation [184], ERK/p38 [183], NF-kappa B [183] and MAPK pathway [176]. More

importantly, it has been discussed that GT has a potential role in inhibition of A fibril/oligomers formation
 25
ACCEPTED MANUSCRIPT
[180, 189-191] and production of non-toxic amyloid oligomers [192]. Table 3 represents summary of some

studies performed in this subject.

4.5.5. Acrylamide

Acrylamide is byproduct of the maillard reaction in certain foods generated by heating for long periods

of time. It has been reported as one of the most crucial carcinogens in human [193, 194]. Reproductive toxicity

[195] and neurotoxicity of the acrylamide through oxidative stress [196-201] has thus far been demonstrated.

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Yassa et al. revealed that GT diminished toxic effect of acrylamide on testicular function. Significant increases

in the testosterone level and animal body weight as well as improvement in the histopathology of the testicles

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were observed when animal rats simultaneously exposed to acrylamide and GT, compared to acrylamide

SC
treatment alone [202]. Interestingly, Esmaeelpanah and her group have attributed the protective effects of GTE,

against neurotoxicity caused by acrylamide exposure both in vivo and in vitro, to antioxidant effects of this

extract [203] (Table 4).

4.5.6. The other neurotoxic agents

U
AN
In addition to the discussed toxic agents, GT and its derivatives have prohibitory effect against a wide

range of neurotoxin components as follow (Table 4): bupivacaine inducing neural injury and neurotoxicity
M

[204], kanamycin (aminoglycoside antibiotics) leading to otoneurotoxicity [205], oxaliplatin [206] and advanced

glycation end products (AGEs) [207] induced neuronal toxicity.

D

The protective effect of EGCG has been determined against quinolinic acid-induced excitotoxic cell
TE

death in N18D3 neuronal cell. In addition, EGCG pre-treatment regulated PI3K and modulated cell survival as

well as death genes (Bcl-2, XL and w, Bax, Caspase-3, 6 and 9) in quinolinic acid exposed cells [208]. More
EP

interestingly, EGCG selectively has neuroprotective effects against apoptosis caused by mitochondrial oxidative

stress. Although, it has been revealed that EGCG did not alter apoptotic insult, induced independent of oxidative
C

stress [209].
AC

4.6. Protective effects of GT and derived components against hepatotoxic xenobiotic

4.6.1. Acetaminophen

Acetaminophen (N-acetyl-p-aminophenol, APAP) is a widely used antipyretic and analgesic drug,

overdose of which can induce severe hepatotoxicity in both humans and experimental animals [210]. Protective

effects of GT and its active constituents have been evaluated in several studies [211, 212]. Orally administered

antioxidants, such as GTPs, protected against APAP liver damages by increasing hepatic GSH levels and
 26
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endogenous S-adenosylmethionine concentrations, as well as reducing severe centrilobular necrosis and the

activity of ALT [213]. Other study demonstrated that EGCG diet (0.54 %, w/w) for one week decreased plasma

ALT and AST activities after acetaminophen administration. EGCG also decreased plasma and liver contents of

acetaminophen-glucuronate and acetaminophen-glutathione [214]. In addition, GTE treatment (500 mg/kg or

1000 mg/kg, by gavage), three hours prior to APAP administration, dose dependently decreased hepatotoxicity

of this drug; while GTE treatment, six hours after APAP administration, increased the toxicity [215].

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Furthermore, another study determined that APAP disturbed metabolism of fatty acid metabolism, bile acid,

phospholipid and energy. GTE pre-treatment restored these metabolite levels to that of control levels. However,

RI
administration of GTE after APAP, induced more changes in the metabolites, compared to APAP alone,

SC
indicating more severe hepatotoxicity [216].

4.6.2. Doxorubicin

Doxorubicin (DOX) is an anthracycline antibiotic, generally used in tumor therapy. It was reported that

U
DOX has hepatotoxicity effects [217]. Regarding that EGCG does not reduce DOX anti-cancer efficacy and it
AN
could reduce DOX hepatotoxicity, the consumption of this GT component during DOX therapy appears to be

safe and helpful. Findings revealed that EGCG (25 M) increased viability of isolated hepatocytes, while it
M

protected these cells against DOX induced hepatotoxicity and ROS production [218]. In addition, studies

indicated that vitamin E and catechin (200 mg/kg/week) significantly reduced DOX induced hepatotoxicity in
D

rats, by alleviation of MDA level and improvement of the impaired antioxidant enzyme levels [219].
TE

4.6.3. Halothane

Halothane, a general inhalational anesthetic, induces liver toxicity. Younes et al. during 1983-1988
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reported that catechin could protect liver against halothane toxicity by inhibiting lipid peroxidation [220],

reduction of serum enzyme elevations, including ALT and sorbitol dehydrogenase [221, 222], improvement of
C

morphological alterations [222] and increase in the concentration of GSH in the liver [221].
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4.6.4. Azathioprine

GTP inhibited Azathioprine (AZA) induced apoptosis and liver injury. It was reported that orally

administered GTPs (100 and 300 mg/kg/day) for 21 days, resulted in significant reduction of ALT and AST,

alkaline phosphatase (ALP) and MDA levels. In contrast, this could elevate hepatic GSH, CAT and GPx.

Moreover, GTP significantly improved serum total proteins and hepatic total antioxidant activity, CAT, TNF-

and caspase3 levels in AZA treated rats. [223].

4.6.5. Ethanol
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Long term ethanol consumption is one of the critical causes of clinical abnormalities, particularly liver

diseases, around the world [224]. Investigations determined that C. sinensis could beneficially protect cells

against hepatotoxicity caused by ethanol [225, 226]. It has also been distinguished that EGCG could reduce the

formation of fatty liver as well as serum levels of AST and ALT, caused by ethanol [227]. Another study

showed that oral administration of ethanol (50%) for five weeks significantly increased in level of liver non-

enzymatic (cholesterol, triglycerides, MDA as well as GST) and enzymatic markers including ALT, AST, and

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ALP. Ethanol also reduced activity of SOD, total proteins and albumin. The aqueous extract of GT (5 and 10

mg/kg) was able to improve the level of these markers and damaged hepatocytes to the normal structure [228].

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4.6.6. Carbon tetrachloride

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Carbon tetrachloride (CCl4), is a classic hepatotoxidant, causing acute liver injury [229].

Administration of CCl4 caused liver necrosis associated with increase in lipid peroxidation, mRNA and protein

levels of inducible nitric oxide synthase, nitrotyrosine, and nitric oxide radicals. EGCG administration (50 and

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75 mg/kg, i.p.) reduced all liver histological and biochemical alterations induced by CCl4 (20 L/kg, i.p.) in
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mice [230]. Investigations implicated the protective effects of GTE (10% in drinking water) on liver damage

induced by CCl4 (1 mg/kg, via gavage) in male hamsters. Thus, lower level of hepatic MDA was observed in
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GTE plus CCl4 treated animals compared to the hamsters exposed by CCl4. GTE supplementation in

combination with CCl4 also decreased serum lipid profiles such as total cholesterol, triglyceride and low density
D

lipoproteins (LDL). Besides, induction of p53 expression by CCl4 was reduced by GTE co-administration [231].
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4.6.7. Vinylidene chloride

Similar to vinyl chloride, vinylidene chloride, is widely used as a monomer for the production of
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plastics while they could cause hepatotoxicity [232]. Study showed that co-administration of dithiocarb plus

catechin (0.2 g/kg, orally) significantly reduced enzymatic serum activity of aminotransferases and sorbitol
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dehydrogenase, caused by vinylidene chloride [233].

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4.6.8. 2-Nitropropane

2-Nitropropane (2NP) is widely used as an industrial solvent which has been detected in tobacco

smoke. Investigations implicated that 2NP could induce hepatotoxicity [234]. In contrast, it has been

demonstrated that GT could reduce side effects of 2NP administration by preventing liver oxidative DNA

damage as well as hepatotoxicity [235, 236]. The elevation of nuclear DNA adducts in liver, caused by 2NP

(100 mg/kg, i.p., single dose), was depressed by green tea in drinking water. Moreover, serum aminotransferases

and LDH augments, caused by 2NP administration, were effectively prevented by GT. GT also reduced the
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elevation of hepatic lipid peroxide levels, increased the hepatic glycogen content and improved the liver

degenerative changes by 2NP [236].

4.6.9. 1,4-naphthoquinone

After exposure of 1,4-naphthoquinone to primary cultured rat hepatocytes, LDH leakage and cell

viability were both improved due to pre-treatment cells with GTE and GTPs. These extracts could also prevent

the reduced protein thiol concentration caused by 1,4-naphthoquinone induction. It was determined that tea

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polyphenols could partially protect hepatocytes against 1,4-naphthoquinone, by regulation of protein thiol level

but not due to the their ability on removing ROS and anti-oxidative activity [237].

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4.6.10. Dextran sulfate sodium

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It has been reported that low (0.01%) and medium (0.1%) concentration of GTPs have valuable effects

on dextran sulfate sodium induced hepatotoxicity, via upregulation of heme oxygenase1 and heat shock protein

70 (HSP70) mRNA expression, as well as suppression of ALT and AST levels. However, these beneficial

effects were disappeared at a high dose (1%) [238].

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4.6.11. Formaldehyde

Formaldehyde is a chemical agent used as a preservative in foods and as a fixative in histopathology

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techniques. This agent is found in many products such as antiseptics, medicines and cosmetics. Findings

indicated that GTE could act as a potent protector against formaldehyde induced hepatotoxicity. Formaldehyde
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treatment (200 mg/kg, i.p.) induced a significant decrease in AST, ALT and GSH, while it caused a significant
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increase in MDA and advanced oxidized protein product levels in mice liver. In addition, some structural

damages, such as hepatocyte degeneration and necrosis, were observed following exposure to formaldehyde.
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Although, investigations demonstrated that the antioxidant activity of GTE (50 and 150 mg/kg, orally) protected

against formaldehyde induced hepatotoxicity [239].

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4.6.12. 4-Nitroquinoline 1-oxide

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4-Nitroquinoline 1-oxide (4-NQO) is a potent experimental oral carcinogen which can lead to lipid

peroxidation following hepatotoxicity. Beneficial properties of GT have been reported against 4-NQO by

reducing marker activities in damaged hepatocyte and improvement of histopathological injuries [240] via

enhancing the cellular thiol status [241].

4.6.13. The other hepatotoxic agents

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Furthermore, protective effect of GT and related catechins against some hepatotoxic drugs, such as

erythromycin estolate, amitriptyline, nortriptyline [242], tamoxifen [243] and isoniazid [244], has been proved

in previous studies.

4.7. Protective effects of GT and its main components against nephrotoxic xenobiotic

4.7.1. Gentamycin

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Gentamycin is an antibiotic used to treat sever gram negative infections, but its nephrotoxicity forces

its usage to become limited. Gentamycin induced nephrotoxicity has been attributed to oxidative stress [245,

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246]. Several studies revealed the protective effects of GT and its contents against gentamycin induced

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nephrotoxicity via improving antioxidant defense [247-252]. In this regards, Veljkovic and his colleagues

determined the preventive effects of GT pre-treatment (300 mg/kg/day, by gavage, 15 days) on gentamycin

induced nephrotoxicity (100 mg/kg/day, i.p., 8 days), through reduction of oxidative stress [247, 253].

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Gentamycin (100 mg/kg/day, i.p. 14 days) increased serum creatinine, blood urea nitrogen and renal oxidative
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stress levels which were accompanied with degenerative changes in glomeruli and tubules. However, catechin

pre-tereatment (50 mg/kg/day, orally, 17 days) revealed renoprotective effects against gentamicin-induced
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nephrotoxicity, likely through its antioxidant action [248]. Besides, in uninephrectomized rats (as a model of

progressive renal failure), GTE (300 mg/kg/day, orally, 30 days) ameliorated nephrotoxicity effect of
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gentamycin (50 mg/kg, B.I.D., s.c, 15 days) [249].

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4.7.2. Cisplatin

Cisplatin, a platinum containing anti-cancer drug, is used to treat various types of solid malignancies.
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However, its serious adverse effects, especially nephrotoxicity, hamper therapeutic application of cisplatin high-

dose. Cisplatin could promote oxidative stress, inflammatory reactions, and tubular cell apoptosis leading to
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renal cell damages, particularly nephrotoxicity [254]. Studies have discussed about the protective effects of GT
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and its secondary metabolites against cisplatin-induced renotoxicity [255-257], with regards to their anti-oxidant

[258] and anti-apoptotic properties [259, 260]. It has been shown that EGCG (100 mg/kg, i.p.) reversed the toxic

effects of cisplatin (20 mg/kg, i.p.) on biochemical factors and kidney damages [259, 260]. EGCG co-treatment

also decreased the expression of phosphorylated-ERK, glucose-regulated protein 78 and caspase-12 by

inhibiting endoplasmic reticulum stress-induced apoptosis [259]. Besides, EGCG attenuates cisplatin induced

apoptosis in the kidney by regulating death receptor, Fas, and subsequently expression of Bax and Bcl-2 [260].

Sahin et al. showed that EGCG supplementation improved cisplatin nephrotoxicity by increasing levels of NF-
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E2-related factor-2 and heme oxygenase-1, as well as decreasing levels of nuclear factor-kappa B and 4-

Hydroxynonenal [261].

4.7.3. Cyclosporine

Cyclosporine is an important immunosuppressive drug from long time ago, although this could cause

severe nephrotoxicity side effects [262]. It has been revealed that GTE has renoprotective effects in

cyclosporine induced nephrotoxicity. GTE improves renal function, by increasing the antioxidant status,

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decreasing peroxidative levels [263, 264] and stimulating mitochondrial biogenesis [265]. Besides, it has been

proposed that protective effects GT in cyclosporine induced nephrotoxicity could be due to the blockage of

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renin-angiotensin-aldosterone system, while its activation plays an important role in cyclosporine induced

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renopathy [266]. Furthermore, protective effects of epicatchin against cyclosporine induced oxidative stress and

nephrotoxicity has been reported. Cyclosporine (50 mg/kg, s.c., 10 days), significantly increased free radicals

and ROS leading to lipid peroxidation and cell damage, while it decreased activity of antioxidant enzymes (i.e.

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SOD, CAT and GPx). However, epicatchin (10 mg/kg, i.p., 10 days) alleviated toxicity of cyclosporine by
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decreasing the lipid peroxidation and enhancing the antioxidants enzyme activities [267]. Mun et al. showed the

protective effects of EGCG in cyclosporine-induced renal dysfunction. Cyclosporine (15 mg/kg/day, s.c., 14
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days) increased blood urea nitrogen, serum creatinine and MDA, while EGCG (25 mg/kg, i.p., 3 days) treatment

significantly reversed these detrimental effects, due to its antioxidant properties [268], a mechanism which has
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recently been proved by El-Mowafy et al. [269].

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4.7.4. Tacrolimus

Tacrolimus is the first choice of immunosuoressive drugs for the lung and/or heart transplant recipients.
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However, its nephrotoxicity side effect is still the main concern in administration of this drug [270]. It has been

shown that tacrolimus (50 M) induced cell death in LLC-PK1 cells (a porcine renal proximal tubule cell line)
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was reduced by addition of GTE (6.25, 12.5, and 25 M) [271]. In addition, it has been determined that co-
AC

treatments with EGCG + EGC, EGCG + ECG, and EGC + ECG synergistically protected LLCPK1 cells from

the nephrotoxicity induced by tacrolimus [272]. Furthermore, it has been demonstrated that tacrolimus (1 mg/kg,

i.p.) induced proteinuria and increased NO and renal MDA production, which was accompanied with decrease

in enzyme activities of SOD and CAT. In contrast, GTE (100 mg/kg, s.c.) could significantly reverse these

impairments [273].

5. Clinical studies
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In a clinical trial, it was revealed that GTPs modulated AFB metabolism and metabolic activation

[274]. It has been reported that toxic and carcinogenic effects of AFB are generally manifested by metabolizing

AFB to the other products in phase 1, although these products could be detoxified by further metabolism in

phase 2 [275]. Aflatoxin M1 (AFM1) and aflatoxin B1mercapturic acid (AFB-NAC) are respectively two major

phase 1 and phase 2 metabolites for AFB, respectively [275, 276]. It was shown that GTPs consumption

increased the ratio of AFB-NAC: AFM1, in comparison with placebo group [274]. Through pervious sections,

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protective/antidotal effects of GT and its secondary metabolites against a wide range of natural toxins,

neurotoxic, cardiotoxic, hepatotoxic and nephrotoxic agents have been proved in experimental studies.

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However, there are poor data about using GT and its constituent as an antidote in clinical studies. In this regard,

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some clinical studies have shown that they have protective potential in inflammatory disorders [277] and

prophylaxis for influenza infection [278], controlling acute radiation-induced esophagitis [279] and ulcerative

colitis [280]. Besides, the consumption of C. sinensis is associated with decrease in cardiovascular risk factors

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[281] and prevalence of cognitive impairment in humans [282]. Topical application of GT extract showed sun
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protection and prevents UV radiation-induced genotoxicity [283]. (table 5)
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6. Conclusion

Several investigations demonstrated that GT and its main compounds, in particular catechin,
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epicatechin, epicatechin gallate, gallocatechin, epigallocatechin, epigallocatechin gallate, have antidotal or

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protective effects against a wide range of environmental or chemical toxins. In this review, we summarized

findings implicating antidotal/protective effects of GT and its constituents against some types of mycotoxins,
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snake venoms, bacterial toxins, metals, fluoride, pesticides, cardiotoxic, neurotoxic, hepatotoxic and

nephrotoxic chemical agents in vivo and in vitro. The protective effects of GT and its compounds were mainly
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attributed to their anti-oxidative, radical scavenging, chelating and anti-apoptotic properties modulating
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inflammatory responses. However, it has also been reported that GT and respective components could

contribute to increasing toxin metabolism and neutralizing PLA2, proteases, hyaluronidase and l-amino acid

oxidase enzymes.

Altogether, broad spectrum studies and controlled clinical trials are required to verify the efficacy of

GT and its secondary metabolites in human, as a worth antidotal/protective agents.

Conflict of interest statement

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The authors declare that there are no conflicts of interest.

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Table 1 Summary of the protective effects of GT and its main components against LPS induced inflammation

Protective Model Protective Results Mechanism Ref.

defense against agent

LPS (0.1-1 3T3-L1 EGCG (10- -Reduced the level of -Suppression of TLR-4 [49]

g/ml) fibroblasts 100 M) inflammatory mediators and signaling via 67-kD laminin

cytokine (IKK, p-NF-B, receptor

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TNF-, and IL-6). -Attenuation insulin-

stimulated glucose uptake

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associated with decreased

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GLUT4 expression

LPS (0.1 g/ml Human Pre-treatment -Suppressed the LPS-induced -Inhibition of LPS-mediated [50]

U
) cerebral with EGCG (1, expression of IL-1 and TNF- NF-B activation

microvascu 5 and 25 M) -Involvement of 67-kD

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lar -Inhibited the expression of laminin receptor

endothelial MCP-1/CCL2, VCAM-1 and

M

cell ICAM-1

(hCMEC) -Induced the expression of

D

line, D3 tight junction proteins

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clone (Occludin and Claudin-5) in

(CMEC/D3 hCMECs.
EP

)
C

LPS (0.5 RAW264.7 Pre-treatment -Reduced the TLR-4 Involvement of 67-kD [51]
AC

g/ml) cells with EGCG (1 expression laminin receptor

M) -Induced a rapid upregulation

of Tollip

LPS (1 g/ml) -RAW EGCG (0.2-10 -Attenuated endotoxin- -Prevention from HMGB1 [54]

264.7 cells M) induced release of HMGB1 accumulation/clustering on

-Balb/C -Inhibited HMGB1-induced macrophage cell surface

mice cytokine release -Attenuation of systemic

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Primary accumulation of pro-

peritoneal inflammatory mediators

macrophag (e.g., HMGB1) and

es surrogate markers (e.g., IL-6

-Human and KC) of lethal sepsis

peripheral -Suppression of HMGB1-

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blood mediated inflammatory

mononucle responses by preventing

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ar cells accumulation of exogenous

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Endotoxemia Balb/C EGCG (4 -Improved animal survival rate HMGB1 on macrophage

(LPS, 15 mice mg/kg, i.p.) cell surface

mg/kg, i.p.)

Sepsis (cecal Balb/C EGCG (4

U
-protected against lethal sepsis
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ligation and mice mg/kg, i.p.) -attenuated sepsis-induced

puncture) systemic accumulation of IL-

M

6, KC, and HMGB1

LPS (1 mg/ml, C57BL/6 EGCG (0.5 -Restored the proliferation and -Suppressing the activity of [55]
D

i.c.v.) mice mg/kg, i.p.) differentiation of neural stem microglia

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cells in the dentate gyrus -Modulating the TLR-4-NF-

-Ameliorated the apoptosis of B pathway

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neural stem cells

-Attenuated pro-inflammatory
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cytokine production
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LPS (0.25 Human EGCG pre- -Diminished the concentration Modulating ERK1/2 and [56]

g/ml) retinal treatment (25, of TNF-, VEGF, MCP-1 and p38 pathways

endothelial 50 and 100 NO

cells M) -Attenuated LPS-induced

activation and phosphorylation

of ERK1/2 and p38

LPS and IFN- Mesangial EGCG pre- -Blocked inflammatory Regulation the Akt/mTOR [58]
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(1g/ml and cells from treatment (50 mediator production (iNOS pathway

300 U/ml, female M) expression, supernatant NO

respectively) MRL/lpr and Il-6)

mice -Inhibited the immune-

stimulated PI3K/Akt/mTOR

pathway

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-Decreased phosphorylation of

Akt

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LPS (15 mg/kg, Sprague EGCG Pre- In midbrain: Reducing TNF- and NO [59]

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i.p.) Dawley treatment (10 -Decreased TNF- and NO inflammatory mediators and

rats mg/kg, i.p.) concentration preserving dopamine level

-Increased dopamine level in midbrain

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-Preserved the number and the
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density of tyrosine

hydroxylase immunoreactive
M

neurons

EGCG: epigallocatechin gallate

D

ERK1/2 : extracellular signal-regulated protein kinases 1 and 2

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GLUT4: Glucose transporter type 4

hCMECs: Human cerebral microvascular endothelial cell

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HMGB1: High mobility group box 1

ICAM-1: Intercellular Adhesion Molecule 1

C

i.c.v.: Intracerebroventricular
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i.p.: Intraperitoneal

iNOS: Inducible nitric oxide synthase

LPS: Lipopolysaccharide

MCP-1/CCL2: Monocyte chemoattractant protein-1

NF-B: nuclear factor-kB

NO: Nitric oxide

PI3K/Akt/mTOR: phosphoinositide 3-kinase/ Protein kinase B/ mammalian target of rapamycin

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p-NF-B: phospho-nuclear factor-kappa B

TLR-4: Toll-like receptor 4

Tollip: Toll-interacting protein

VCAM-1: vascular cell adhesion molecule 1

VEGF: Vascular endothelial growth factor

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C EP
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Table 2 Protective effects of GT and relevant components against doxorubicin induced cardiotoxicity

Protective Model Protective Results Mechanism Ref.

defense agent

against

DOX (15 Wistar rat EGCG (40 -Improved EKG and Suppressing [135]

mg/kg, i.p.) (200- 250 mg/kg, orally) histopathological changes oxidative stress,

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g) -Decreased cardiac enzyme inflammation and

concentration (CKMB, and LDH) apoptotic signals as

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-Ameliorated oxidative stress well as activation of

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injury pro-survival

-Increased ErbB2 expression and pathways

HSP 70 level

U
-Decreased the level of p53 calpain
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2, caspase 3 and 12

DOX (3 Wistar rat GT extract -Improved hemodynamic Anti-oxidant activity [136]

M

mg/kg, i.p.) (200- 250 (100 mg/kg, parameters and EKG changes

g) orally) -Decreased serum markers of

D

cardiotoxicity (LDH, CK, SGOT)

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and lipid peroxides

-Increased the activities of

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antioxidant enzymes
C

DOX (1 or Wistar rat GT extract in -Improved the change in blood Anti-oxidant activity [137]
AC

2 mg/kg, (165-195 g) drinking water fatty acid-binding proteins, brain

i.p.) (163 natriuretic peptide, and SOD level

mg/kg/day)

DOX (1 Ventricles Pre-incubation -Decreased LDH activity Alleviating ROS [138]

M) from with EGCG -Increased cell viability, protein production,

neonatal (38 M) expression and activities of apoptosis, and

rats manganese superoxide dismutase increasing activities

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(Sprague- (MnSOD), catalase, and and protein

Dawley rat, glutathione peroxidase expression of

1-3 days -Decreased MDA content and ROS endogenous

old) production and apoptosis antioxidant enzymes

DOX (20 Wistar rat GT extract -Decreased the levels of AST, CK, Accelerating heart [139]

mg/kg i.p.) (200-250 g) (100, 200 and LDH, LPO, cytochrome P450 anti-oxidant defense

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400 mg/kg, -Increased the activities of GPx, mechanisms and

orally) SOD and CAT, glutathione down regulating the

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reductase, glutathione s- LPO to the normal

SC
transferase, in heart levels.

DOX (13 Wistar rat Catechin (10 -Decreased MDA level Anti-oxidant and [141]

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mg/kg) (200-230 g) mg/kg, orally) -Increased glutathione peroxidase, anti-inflammatory

CAT and SOD activities properties

AN
-Decreased the expression levels of

inflammatory cytokines (NFkB,

M

TNF- and iNOS)

DOX (3 Sprague- Catechin (10, Especially at low dose levels: Anti-oxidant and iron [142]
D

mg/kg, i.v.) Dawley rat 100, 200 and -Decreased Q-T interval chelating activities.
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(210-230 g) 500 mg/kg, -Improved the contractile

i.p.) performance of isolated atria

EP

-Improved heart ultrastructural

lesion
C

DOX (1 Ventricles GT extract (10 -Decreased LDH release Modifications in the [146]
AC

M) from or 50 g/ml) -Decreased conjugated fatty acyl pattern

neonatal rat dienproduction (indicator of lipid

(Wistar rat, peroxidation)

2-4 days -Increased highly unsaturated fatty

old) acids

-Increased unsaturation

index
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AST: aspartate aminotransferase

CAT: catalase,

CK: creatine Kinase

CKMB: creatine Kinase-MB

DOX: doxorubicin

EGCG: epigallocatechin gallate

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EKG: electrocardiogram

ErbB2: receptor tyrosine-protein kinase erbB-2

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GPx: glutathione peroxidase

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GT: green tea

HSP 70: 70 kilodalton heat shock proteins

iNOS: inducible nitric oxide synthase

LDH: lactate dehydrogenase

U
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LPO: lipid peroxidation

MDA: malondialdehyde
M

MnSOD: manganese superoxide dismutase

NFkB: nuclear factor-kB

D

ROS: reactive oxygen species

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SGOT: aspartate aminotransferase

C EP
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Table 3 Protective effects of GT and related components against Amyloid -induced neurotoxicity

Protective Model Protective agent Result Mechanism Ref.

defense against

AB25-35 (20 Mice EGCG pre- Attenuated release of Anti-oxidative function [177]

M) cortical treatment (3, 10 LDH

culture and 30 M)

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AB25-35 (100 Wistar rat Epicatechin Decreased lipid Anti-oxidant effects [178]

M/l into (280-300 pre-treatment peroxidation, ROS,

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hippocampal g) (30 mg/kg, oxidative damages and

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region) orally) glial-fibrilar acidic

protein

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immunoreactivity in rat

hippocampus,
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improved memory

skills
M

AB1-42 (25 M) Primary EGCG pre- -Increased cell viability Activation of 7 nAChR [185]

cortical treatment (80 -Reduced number of and PI3K/AKT

D

neurons M) apoptotic cells Signaling Cascade

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culture -Decreased ROS

generation
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-Downregulated

caspase-3 levels
C

-Improved activation
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of 7 nAChR, PI3K,

Akt and Bcl-2

Abeta1-42 (2 Eight- L-theanine pre- -Attenuated Abeta 1-42- Suppression of ERK/p38 [183]

g/mouse, week-old treatment (2 induced memory and NF-kaB as well as

i.c.v) male and 4 mg/kg, impairment the reduction of

Slc:ICR orally) in the -Reduced Abeta1-42- macromolecular

mice drinking water induced neuronal cell oxidative damage

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death in the cortex and

hippocampus of the

brain

-Inhibited ERK and

p38 MAPK as well as

the activity of NFkB

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-Reduced oxidative

protein and lipid

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damage and the

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elevation of

glutathione levels in

the brain

EGCG: epigallocatechin gallate

U
AN
ERK: extracellular signal-regulated kinase

i.c.v : Intracerebroventricular
M

LDH: lactate dehydrogenase

MAPK: mitogen-activated protein kinase

D

nAChR: nicotinic acetylcholine receptors

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NF-kappaB: nuclear factor kappaB

PI3K: phosphatidylinositol 3-kinase

C EP
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Table 4 Protective effects of GT and respective components against xenobiotic induced neurotoxicity

Protective Model Protective agent Result Proposed Refere

defense against Mechanisms nces

Acrylamide (10 PC12 cells GT extract pre Increased cell viability Suppression of [203]

mM) treatment (31.2 reactive oxygen

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and 62.5 g/ml) species (ROS)

Acrylamide (50 Male GT extract -Reversed gait abnormalities generation

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mg/kg, i.p.) Wistar rats (6.25-12.5-25- -Counteracted decrease in

(200-250 50 mg/kg, i.p.) body weight

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g)

Bupivacaine (1 Neuroblast EGCG pre- -Reduced ROS formation Anti-apoptotic [204]

U
mM) oma cells treatment -Increased phosphorylation effects
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(N2a and (10-50 M) of Akt and GSK-3

SH- -Down-regulated PTEN

SY5Y) -Activated PI3/Akt signaling

M

Kanamycin (500 Sprague Catechin (400 -Increased densities and - [205]

D

mg/kg, gavage) Dawley mg/kg, gavage) numbers of efferent nerve

for 14 days rat for 14 days fibers and terminals

TE

Oxaliplatin (4 Sprague- Co-treatment -Decreased elevated thermal Alleviate acute [206]

EP

mg//kg, i.p.) Dawley with GT (300 threshold values functional

rat mg/kg, orally) -Decreased elevated sensory channelopathy of

C

threshold axonal Na+ channels

AC

AGEs (500 Human Treatment with -Decreased ROS formation -Antioxidative [207]

g/ml) neuroblast EGCG (5 and -Upregulated intracellular properties

oma cell 10 M) CAT and SOD levels and -Interfering with

line SH- activity AGEs-RAGE

SY5Y -Decreased malondialdehyde interaction mediated

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and carbonyl levels and pathways

AGEs -Downregulated the

mRNA level of AGE

receptor,

Quinolinic acid N18D3 EGCG pre- -Increased cell viability -Blocking increase [208]

(30 mM) neural treatment (1- -Protected the cells from of intracellular

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cells 100 M) apoptotic death calcium levels

-Reduced excitotoxic cell -Inhibiting NO

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death production.

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-Prevented expression of the

proapoptotic gene, caspase-9,

-Increased antiapoptotic

U genes, Bcl-XL, Bcl-2, and

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Bcl-w.

-Increased immunoreacitivity
M

of PI3K

AGEs: Advanced glycation end products

D

CAT: catalase
TE

EGCG: epigallocatechin gallate

GSK-3: Glycogen synthase kinase 3 beta

EP

PI3: phosphoinositide 3-kinase

SOD: superoxide dismutase

C
AC
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Table 5 Protective effects of GT and respective components in some clinical studies

Type of Number of patients intervention results Refere

study nce

Prospective 120 healthy adults, green tea polyphenols -Significant elevation in [274]

study aged 20-55 (GTPs) therapy for 3 month the ratio of AFB-

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NAC:AFM1 were found in

GTPs groups compared

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with the placebo group

-GTPs effectively modulate

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AFB1 metabolism and

metabolic activation.

Prospective 20 healthy subjects,

U
Green tea extract daily for The capacity of circulating [277]
AN
study aged 20-55 14 days leukocytes to release both

myeloperoxidase and
M

lactoferrin was increased

D

significantly
TE

Prospective 197 healthy adults, over Catechins/theanine capsules -The incidence of clinically [278]

study 20 years of age for 5 month defined influenza infection

EP

(significantly) and laboratory-

confirmed influenza infection

C

(not significantly) decreased

AC

Prospective 24 patients which have EGCG was given 2 h -Dramatic regression of [279]

study the seventh edition of before the daily radiation esophagitis was observed

American Joint for an average of 34.8 days -The pain score was also

Committee on Cancer reduced

stage IIIA and IIIB

Prospective 20 patients with Received EGCG daily for -Resulted a therapeutic benefit [280]
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study ulcerative colitis 56 days for patients who were refractory

to 5-aminosalicylic and/or

azathioprine.

Prospective 111 healthy adult Received capsule of -Decreased systolic and [281]

study volunteers, 21-70 years Camellia sinensis for 3 diastolic blood pressures by 5

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old weeks and 4 mmHg, respectively

-Decreased serum amyloid

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alpha and malondialdehyde

-There were reductions in total

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and low density lipoprotein

cholesterol

Retrospectiv 1003 subjects aged > or

U
All the subjects were There was a reverse association [282]
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e study =70 y categorized according the between consumption of green
M

history of GT consumption and prevalence of cognitive

impairment
D
TE
C EP
AC
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PT
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U SC
AN
M
D
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C EP
AC

Fig. 1. Chemical structures of the main secondary metabolites of green tea (Camellia sinensis)
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Fig. 2. Green tea and natural toxins: Green tea and its secondary metabolites exhibit antidotal effects against

several natural toxins which attributed to their effects on the toxin metabolism, their anti-oxidative, and anti-
M

inflammatory properties as well as neutralizing PLA2, proteases, hyaluronidase and l-amino acid oxidase

enzymes. They have positive effects on the antioxidative enzymes activity (GPX, SOD, CAT) and decline the
D

ROS generation pathways (NOS, LOX, COX). Besides, by destruction of botulinum membrane they have the
TE

ability to decrease the number of C. botulinum spores. GT and its main secondary metabolites by activating

67LR, blocking TLR-4-NFB signaling pathway and attenuating activation of MAPKs could modulate LPS-
EP

induced inflammatory responses (details have been explained in the text)

Activating sign:

Blocking sign:
C
AC

Green tea or its main secondary metabolites:

CAT: catalase

CD14: cluster of differentiation 14

GPX: glutathione peroxidase

GT: green tea

COX: cyclooxygenase

LBP: Lipopolysaccharide binding protein

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LOX: lipoxygenase

LPS: lipopolysaccharide

67LR: 67-kDa laminin receptor

MAPK: mitogen-activated protein kinas

MyD88: myeloid differentiation primary response gene 88

NOS: nitric oxide synthases

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PLA2: phospholipases A2

ROS: reactive oxygen species

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SOD: superoxide dismutase

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TLR-4: toll-like receptor 4

Tollip: toll interacting protein

U
AN
M
D
TE
C EP
AC
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U SC
Fig. 3. Green tea and chemical toxins: GT and its secondary metabolites have protective effects against a wide
AN
range of chemical toxins (details have been explained in the text). Their mechanisms of protective effects

against toxic agents could mainly be attributed to their anti-oxidant and chelating properties. Modulating
M

apoptosis pathways, improving scavenging reactive oxygen species and enhancing anti-oxidants (CAT, SOD,

and GPX) are the other engaged protective mechanisms. Besides, by modifying cardiomyocyts fatty acid
D

pattern in favor of HUFAs, they have membrane stabilizing effects. GT and its related secondary metabolites
TE

have antidotal effects against A induced neurotoxicity via production of non-toxic amyloid oligomers and

inhibition of A fibril/oligomers formation. By activating PKC, they increased -secretase activity which is part
EP

of non-amyloidogenic pathway in APP processing. Activation of 7 nAChR and inhibition of the NMDA

receptors are the other protective mechanisms. Inhibiting NMDA receptors and regulating iron related proteins
C

are proposed protective mechanisms against glutamate and 6-OHDA induced neurotoxicity, respectively.
AC

Furthermore, by inhibiting dopamine transporters they block MPP uptake and its neurotoxicity. The antidotal

effects of GT and its components against nephrotoxic agents could be attributed to stimulating of mitochondrial

biogenesis, inhibition of death receptors, Fas, and endoplasmic reticulum stress-induced apoptosis

Activating sign:

Blocking sign:

Green tea or its main secondary metabolites:

A: amyloid
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AKT: protein kinas B

APP: amyloid precursor protein

Cis: cyclosporine

COX: cyclooxygenase

CAT: catalase

DAT: dopamine transporter

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DMT1: divalent metal transporter 1

DOX: doxorubicin

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ER: endoplasmic reticulum

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ERS: endoplasmic reticulum stress

FasR: FAS receptor

GPX: glutathione peroxidase

GT: green tea

U
AN
GRP78: 78 kDa glucose-regulated protein

GSK: glycogen synthase kinase

M

HUFA: high unsaturated fatty acids

LOX: lipoxygenase
D

MAPK: mitogen-activated protein kinas

TE

MMP: mitochondrial membrane potential

MPP: 1-methyl-4-phenylpyridinium
EP

nAChR: nicotinic acetylcholine receptor

NMDA receptor: N-Methyl-D-aspartate receptor

C

NOS: nitric oxide synthases

AC

6-OHDA: 6-hydroxydopamine

PI3K: phosphoinositide 3-kinase

PKC: protein kinas C

ROS: reactive oxygen species

SOD: superoxide dismutase

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Highlights

- Green tea and its main compounds have antidotal and protective effects against environmental and

chemical toxins

- These effects are attributed to their antioxidant and chelating properties, enzyme inhibition and

receptor-mediated

- Green tea and its main compounds have a good prospective to introduce as worth antidotal/protective

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agents in human

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M
D
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C EP
AC