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TOKSIKOLOGI DAN AGROMEDIS

Al Munawir FK UNIVERSITAS JEMBER

Toksikologi
Ilmu ttg , deteksi, efek , dan mekanisme kerja racun atau zat kimia beracun. Racun dan obatbeda dosis.

AGROMEDIS
AGROMEDICINE Pertanian, peternakan, perikanan. KEDOKTERAN AGROINDUSTRI KOMUNITAS AGROINDUSTRI MEMECAHKAN MASALAH KEDOKTERAN DAN KESEHATAN PADA MASYARAKAT AGROINDUSTRI PADA PASIEN SIMULASI DALAM KONTEKS PELAYANAN PRIMER DAN KEDOKTERAN KELUARGA

FAKULTAS KEDOKTERAN UNIV. JEMBER


KOMISI PENGEMBANGAN AGROMEDIS KOMISI PENDIDIKAN KEDOKTERAN KOMISI KARYA TULIS ILMIAH KOMISI BIMBINGAN DAN KONSELING GUGUS PENJAMIN MUTU KOMISI ETIK PENELITIAN KESEHATAN KOMISI TEKNOLOGI INFORMASI KOMISI KETRAMPILAN KLINIK

MASALAH AGROMEDIS:
PERILAKU komunitas agroindustri PESTISIDA (produk, tanah, air, udara) 1500 macam pestisida yang tercatat Produk pertanian hasil rekayasa genetik

Figure 8-1 Human exposure to pollutants. Pollutants contained in air, water, and soil are absorbed through the lungs, GI tract, and skin. In the body they may act at the site of absorption but are generally transported through the bloodstream to various organs, where they may be stored or metabolized. Metabolism of xenobiotics may result in the formation of watersoluble compounds that are excreted or in activation of the agent, creating a toxic metabolite.

Downloaded from: StudentConsult (on 9 April 2013 03:17 AM) 2005 Elsevier

Figure 8-2 Xenobiotic metabolism. Xenobiotics can be metabolized to nontoxic metabolites and eliminated from the body (detoxification). However, their metabolism may also result in activation of the chemical leading to formation of a reactive metabolite that is toxic to cellular components. If repair is not effective, short- and long-term effects develop. (Based on Hodgson E: A Textbook of Modern Toxicology, 3rd ed. Fig. 1-1. Hoboken, New Jersey, John Wiley & Sons, 2004.)

Downloaded from: StudentConsult (on 9 April 2013 03:17 AM) 2005 Elsevier

Peran CYPs enzymes subFamily

Biotransformation Xenobiotic metabolism


Essentials of Toxicology
by Klaassen Curtis D. and Watkins John B

Chapter 6

Biotransformation
Water soluble xenobiotics are easier to eliminate ( t1/2)
Urine, feces but not exhalation If within barrier, no out

Multiple enzymes (families)


Constitutively expressed Inducible Broad specificity Polymorphic (allelic variants) Stereo-isomer specificity: 6-OH in hormones:

CYP2A1 CYP3A

6-OH 6-OH

Biotransformation
Potentially toxic xenobiotic Detoxification
Inactive metabolite Relatively harmless Metabolic activation Reactive intermediate

Converting lipophilic to water soluble compounds


Lipophilic Xenobiotic
Phase I - Activation Reactive intermediate Phase II - Conjugation Conjugate Water soluble (polar) (non-polar)

Excretion

Phase I
introduction of functional group
hydrophilicity increases slightly may inactivate or activate original compound major player is CYP or mixed function oxygenase (MFO) system in conjunction with NAD(P)H location of reactions is smooth endoplasmic reticulum

Phase II
conjugation with endogenous molecules (GSH, glycine, cystein, glucuronic acid) hydrophilicity increases substantially neutralization of active metabolic intermediates facilitation of elimination location of reactions is cytoplasm

Phase I reactions
Oxidation
Hydroxylation (addition of -OH group) N- and O- Dealkylation (removal of -CH side chains) Deamination (removal of -NH side chains) Epoxidation (formation of epoxides) Oxygen addition (sulfoxidation, N-oxidation) Hydrogen removal

Table 6.1

O C C

epoxide

Reduction
Hydrogen addition (unsaturated bonds to saturated) Donor molecules include GSH, FAD, NAD(P)H Oxygen removal

Hydrolysis

Splitting of C-N-C (amide) and C-O-C (ester) bonds

See also Chapter 6 of Casarett and Doulls Toxicology

Biotransformation
Activation of xenobiotics is a key element (e.g. benzene, vinyl chloride)
Reactive intermediates include epoxides and free radical species (unpaired electrons) that are short-lived and hence highly reactive Protection is provided by
endogenous antioxidant substances, e.g. GSH vitamins C and E antioxidant enzymes, SOD, GPX, CAT in coupled reactions

Antioxidant molecules are oxidized in the process but have the capacity to regenerate the reduced form from the oxidized - NAD(P)H is a key player
See also p. 40-44 of Casarett and Doulls Toxicology

Cytochrome P450 (CYP) Mixed Function Oxidases (MFO)


Located in many tissues but highly in liver ER Human: 16 gene families CYP 1,2,3 perform drug metabolism >48 genes sequenced Key forms: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 Highly inducible
Alcohol Dioxin/PCBs Barbiturates CYP2E1 CYP1A CYP2B

CYP genes have multiple alleles (2D6 has 53, and 2E1 has 13)

The CYP-450 reaction cycle


A G (B) C F E

Oxidation of vinyl chloride to an epoxide

Metabolic enzymes
1. Microsomal:
1. 2. CYP450 monooxygenases Flavin monooxygenase

2. Non-microsomal
1. 2. 3.
1. 2. 3.

Alcohol dehydrogenase Aldehyde dehydrogenase Monoamine and diamine oxidases


Esterases and Amidases Prostaglandin synthase Peroxidases

3. Both

Cooxidation of acetaminophen by prostaglandin endoperoxide synthetase


Compare to fig. 6-2

Hydrolysis of esters and amides

Hydrolysis of organophosphates

Hydrolysis of epoxides

Stereoselective hydroxylation

Metabolism of benzo(a)pyrene to 9,10 epoxide: Potent mutagen that binds DNA

Azo- and nitro- reduction

Intestinal flora as part of biotransformation

Ready for elimination

Flora action

Oxidation reactions

Benzene trasformation to leukemiacausing metabolite

Flavin mono-oxygenases (FMO) catalyzed reactions

Nitrogen compounds

Phase II reactions
Glycoside conjugation - glucuronidation Sulfate - sulfation Glutathione (GSH) Methylation Acylation
Acetylation Amino acid conjugation Deacetylation

Phosphate conjugation

Glucuronidation of phenol

Sulfation of phenol and toluene

GSH conjugation of acetaminophen

Glutathione
-glutamyl-cysteinyl-glycine

Active site of a GST:

METABOLISM AND INTERACTIONS OF PESTICIDES IN HUMAN AND ANIMAL IN VITRO HEPATIC MODELS
Khaled M Abass

Profenofos, diuron and carbosulfan


By CYP enzym menjadi metabolit lebih toksik/ karsinogenik. Desthiopropylprofenofos, N-demethyldiuron, carbofuron

PERAN INDIVIDUAL ENZYM:


CYP3A4 AND CYP2C19profenofos and carbosulfan CYP1A2 AND CYP2C19.diuron