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Introduction:
The liver is one of the largest and most important organs in the human body. It is
located behind the lower right section of the ribs. The liver performs a wide range of
metabolic activities required for homeostasis, nutrition and immune defense. For
example, it is important in the removal and breakdown of toxic materials from the
blood and the regulation of blood glucose and lipids, the storage of certain vitamins,
iron, and other micronutrients, and in breaking down or modifying amino acids. It is
involved in a plethora of other biochemical reactions1.
The liver is the central organ for detoxification and clearance of exogenous and
endogenous substances, constitutes a primary target for toxic reactions, the major liver
diseases are hepatitis, cirrhosis, and dysfunctions related to bile secretion. Hepatitis is
characterized as an inflammation of the liver that can be present with or without
cirrhosis. Many different drugs can cause drug-induced hepatitis. Painkillers and fever
reducers that contain acetaminophen are a common cause of liver inflammation.
Forms of viral hepatitis include hepatitis A, B, and C. Cirrhosis is a state in which the
tissue in the liver breaks down, becoming fatty and fibrous which can lead to liver
failure.
According to NWHIC (National Women's Health Information Center ) more
than 60,000 Americans die each year due to liver failure, Global prevalence of chronic
hepatitis C is estimated to average 3%. There are some 175 million chronic HCV
carriers throughout the world, of which 2 million are in the USA and 5 million in
Western Europe. HCV accounts for 20% of cases of acute hepatitis, 70% of cases of
chronic hepatitis, 40% of cases of end-stage cirrhosis, 60% of cases of hepato-
cellular carcinoma and 30% of liver transplants. Incidence of new symptomatic
infections has been estimated to be 1–3 per 100 000 persons annually 2. According to
(NCHS, CDC) there are 27,035 deaths from alcohol related chronic liver disease and
cirrhosis each year in the US (Deaths: Final Data for 2001, NCHC, CDC).

Botanicals have been used traditionally by herbalists and indigenous healers

worldwide for the prevention and treatment of liver diseases. Clinical research in this
Century has confirmed the efficacy of several plants in the treatment of liver diseases.
Silybum marianum (milk thistle) is one of the medicinal plants that has been shown to
have clinical applications in the treatment of toxic conditions of the liver12. Silymarin
may be used in many cases of liver diseases and injury, including hepatitis, cirrhosis,
and jaundice. Helps repair liver cells damaged by alcohol and other toxic substances.
Silymarin has been shown to protect animal livers against the damaging effects of
carbon tetrachloride, alcohol, drugs such as paracetamol, and the toxins α-amanitin
and phalloidin found in the death cap fungus (Amanita phalloides). Silymarin also
keeps new liver cells from being destroyed by these same substances, reduces hepatic
inflammation and has potent antioxidant effects11.

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History:
Silybum is cited as one of the oldest known herbal medicines. Dioscorides first
described the plant. In Roman times, Pliny the Elder (A.D. 77), a noted naturalist,
described the medicinal uses of milk thistle, indicating it was “excellent for carrying
off bile.” Culpeper (1650) wrote of its effectiveness in removing obstructions of the
liver and spleen12.

Botany:
Silybum marianum is currently the most well researched plant in the treatment
of liver diseases.The genus Silybum is a member of Compositae family (Asteraceae).
The plant itself is a stout thistle, growing one to three meters tall in rocky soils, with
large purple flowering heads (Figure below). The leaves are characterized by distinct
white “milky” veins that give the plant its common name (milk thistle)14. The active
constituents of milk thistle are flavonolignans including silybins, isosilybins,
silydianin, and silychristine, collectively known as silymarin.Silybin and isosilybin
have two isomers. Silybin is the component with the greatest degree of biological
activity11. Silymarin is found in the entire plant but is concentrated in the fruit and
seeds. Silybum seeds also contain 20–30% essential fatty acids such as Linoleic acid,
oleic acid and palmitic acid9.

Silybum marianum
Kingdom: Plantae
Phylum: Magnoliophyta
Class: Magnoliopsida
Order: Asterales
Family: Asteraceae
Genus: Silybum
Species: marianum

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Chemistry:
Chemical constituents9:

Physicochemical properties:

The anhydrous silybin has mp 158°C and it decomposes at 180°C. Its physical
characteristics are as follows: Its UVmax (in methanol): 288 nm. It is soluble in
acetone, ethyl acetate, methanol, and ethanol and found to be sparingly soluble in
chloroform. It is practically insoluble in water16.

Extraction of flavonolignans
The typical silymarin extraction process involves the defatting of the seeds in a
Soxhlet extraction with petroleum ether for 4 hours followed by a second Soxhlet
extraction with methanol for 5 hours18.

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Pathophysiology:

Liver is a major detoxifying organ in the body, so it’s under a high risk of
toxicity; some causes include drugs, chemicals, free radicals, radiation, metals. free
radicals cause peroxidation of cell membrane lipids of hepatocytes which contain
unsaturated lipids such as phospholipids, this will lead to a free radical chain reaction
and damage the cell membrane, severe exposure to free radicals may cause cancer
because these free radicals may cause peroxidation of nuclear membrane of
hepatocytes and attack the DNA and make mutations in the sequence of DNA2,5 .
Destruction of hepatocytes will lead to exposure of its content to the interstitial fluid
and this is characterized by a buildup of liver enzymes in the blood, these enzymes
include aspartate aminotransferase (AST),alanine aminotransferase (ALT) and
alkaline phosphatase 3.

When liver function tests are assesed , four general patterns are apparent:

1. acute hepatitis pattern, which has elevated transaminase levels and variable
increases in other enzymes
2. cirrhosis pattern, which has decreased albumin, elevated gamma globulins.
3. chronic hepatitis pattern, which has a combination of changes seen in acute
hepatitis and cirrhosis patterns
4. obstructive liver disease pattern, also called cholestasis, which has an elevated
ALP and bilirubin19.

One of the major causes of liver diseases and toxicities is ethanol, metabolism
of ethanol produces acetaldehyde, acetaldehyde promotes GSH depletion,it has also
been shown to stimulate collagen synthesis by liver stellate cells, which might be
involved in the pathogenesis of ethanol-induced liver cirrhosis. ethanol oxidation not
only reduces gluconeogenesis but also accelerates triglyceride synthesis from free
fatty acids, which leads to an accumulation of fat in the liver parenchyma5.

mushroom poisoning by Amanita phalloides, Amanita mushrooms possess two

extremely powerful hepatotoxins, amanitin and phalloidin, Amatoxin poisoning
produces massive hepatic necrosis, Once inside the cell, α – amanitin inhibit
transcription of DNA, resulting in the inhibition of protein synthesis and cell
necrosis5.

Hepatocytes contain certain residues called Glutathione which neutralizes free

radicals, the ability of glutathione decreases in alcoholic persons as it suppresses the
function of glutathione and they become more susceptible to toxicity 4,5.

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Pharmacology:

Pharmacokinetics:
Silymarin is not water soluble so it cannot be taken as a tea.The absorption with
oral administration is rather low with only 2%-3% of the silybin recovered in 24
hours from rat bile. The peak plasma levels after an oral dose are achieved in 4-6
hours in both human and animals. Silymarin is cleared from the body predominantly
via bile and to a lesser extent the kidneys. The half-life of silymarin is 6-8 hours12.
Silymarin is complexed with phospholipids like phosphatidylcholine give rise to a
new drug delivery technology called phytosome showing much better absorption
profile following oral administration owing to improved lipid solubility which enables
them to cross the biological membrane, resulting enhanced bioavailability i.e. more
amount of active principle in the systemic circulation20,also SMEDDS(self-
microemulsifying drug delivery system) could be use to improove solubility of
silymarin,The basic principle of this system is spontaneous formation of an emulsion
in the gastrointestinal tract that presents the drug in a solubilized form21.

Pharmacodynamics:

Mechanisms of action22
The flavonolignans of Silybum marianum have hepatoprotctive activity, their
mechanisms of action include
1. As antioxidants, free radical scavengers and regulators of the intracellular
content of glutathione.
2. as cell membrane stabilizers and permeability regulators that prevent
hepatotoxic agents from entering hepatocytes;
3. As promoters of ribosomal RNA synthesis, stimulating liver regeneration.
4. as inhibitors of the transformation of stellate hepatocytes into myofibroblasts.

Antioxidant activity
Silymarin and silibinin (silybin) are antioxidants that react with free radicals
transforming them into more stable and less reactive compounds. Silymarin and
silybin have been reported to inihibit lipid peroxidation. In rats, intraperitoneal
silymarin has been shown to increase total glutathione in the liver, intestine and
stomach and to improve the reduced glutathione to oxidised glutathione ratio9.

Stimulation of liver regeneration:

One of the mechanisms to explain the ability of silymarin to stimulate the
regeneration of hepatic tissue is the increase in protein synthesis in damaged livers.it
has been demonstrated that Silybin binds to a regulative subunit of RNA-polymerase
and activates this enzyme; as a consequence the synthetic rate of ribosomal RNA is
enhanced leading to an increased formation of intact ribosomes which result in
increased protein synthesis6.

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Membrane stabilizing activity:
In case of mushroom poisoning silymarin is able to protect liver from damaging
effects of this mushroom because silymarin stabilizes the cell membrane of
hepatocytes ,thus inhibit entry of the toxins22.

Antifibrotic effects:
Silybin was found to reduce the proliferation of freshly isolated rat hepatic
stellate cells by about 75 percent. It also reduced the conversion of stellate cells into
myofibroblasts.

Anti-inflammatory effects:
Silymarin has been shown to have significant anti-inflammatory effects on
hepatic tissue by inhibition of neutrophil migration, inhibition of Kupffer cells,
marked inhibition of leukotriene synthesis and formation of prostaglandins, the
inhibitory effect on 5-lipoxygenase pathway resulting in inhibition of leukotriene
synthesis12.

Inhibition of cytochrome P450:

silymarin has an inhibitory effect on the cytochrome P450 (Phase I)
detoxification system, it will inhibit p450 reversibly. silymarin and other
antioxidants afford some protection against the free radicals generated by P450
enzymes10.

Dosing:
The typical dose for silymarin is 240-900 mg/day in two or three divided doses. 15.

Toxicity:

Even in large doses silymarin is devoid of toxic effects and in particular has no
harmful action on the embryo. In isolated cases, a mild laxative effect has been
observed15. Two separate clinical trials of milk thistle in pregnant women yielded
positive results with no evidence of harmful effects on the pregnancy8.

Conclusion:

*Silybum marianum is an important plant for protection of an important organ, which

is liver

* It is a very familiar plant ,very cheap ,can easily be achieved even by non practiced
persons, and be used to its important purposes.and we should know that kurdistan is
rich with this plant so we should take in mind that it can be used for this purpose in a
scientific way.

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References:

1. Susan Standring, (2008).Gray's Anatomy the Anatomical Basis of Clinical Practice, 40th
edition, Elsevier.
2. Sherlock S, Dooley J., (2002).Diseases of the Liver and Biliary System, 11th edition.P
305, Blackwell.
3. Marilyn Barrett, (2004).The Handbook of Clinically Tested Herbal Remedies volume
1,p 933-936, Haworth Press.
4. McPhee, Ganong, William F.,Stephen J.,(2006) Pathophysiology of Disease: An
Introduction to Clinical Medicine, 5th edition. McGraw-Hill.
5. Frank A. Barile, (2005). Clinical toxicology: principles and mechanisms, 266CRC Press.
6. James E.Robbers,Marilyn K.Speedie,Varro E. Tyler,(1996).Pharmacognosy and
pharmacobiotechnology.First Edition,Williams and Wilkins a Waverly company.
7. Vinay Kumar, Abul K. Abbas, Nelson Fausto, Richard Mitchell, (2007). Robbins Basic
Pathology.8th Edition, Elsevier.
8. Aviva Romm, (2010). Botanical medicine for women’s health,p 591, Elsevier.
9. Joanne Barnes, Linda A. Anderson, J David Phillipson,(2007).Herbal Medicines.Third
edition,p 429-434, Pharmaceutical Press.
10. Lasley Braun,Marc Cohen,(2007). Herbs and natural supplements.second edition,p 1039-
1049,Elsevier.
11. Dewick P. M., (2009). Medicinal natural products a biosynthetic approach.third edition,
p 174-176,John Wiley & Sons.
12. S. Luper, (1998).A review of plants used in the treatment of liver diseases: Part 1, Altren
Med Rev 3: 410-421.
13. http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/phenol/flavonoid.html
14. Lidia Radko, Wojciech Cybulski, (2007). Application of sylimarin in human and animal
medicine. Journal of Pre-Clinical and Clinical Research, Vol 1, No 1, 022-026.
15. Ikhlas A. Khan, Ehab A. Abourashed, (2010). Leung's Encyclopedia of Common Natural
Ingredients: Used in Food, Drugs and Cosmetics. Third Edition,p 439-442, John Wiley
& Sons.
16. Ashutosh Kar, (2007).Pharmacognosy and pharmacobiotechnology.Second Edition,p
365,new age international publishers.
17. WHO monographs on selected medicinal plants. Volume2. World health Organisation
Geneva, 2002, p 306-307.
18. Donald G. Barceloux,( 2008).Medical toxicology of natural substances, p 553-557, John
Wiley & Sons.
19. Walter L. Kemp, Dennis K. Burns, Travis G. Brown,(2008).The big picture pathology,p
261-262, McGraw-Hil.
20. Sindhumol P. G., Maria Thomas, Mohanachandran P. S.,(2010), phytosomes: a novel
dosage form for enhancement of bioavailability of botanicals and neutraceuticals,
international journal of pharmacy and pharmaceutical sciences, Vol 2, Issue 4, 2010,
ISSN- 0975-1491.
21. 2.Xin-Ru Li, Yu-Sheng Pei, Yan-Qing Huang, Yan-Xia Zhou, Yu-Chen Zhang, Yan
Liu,( 2009). In vitro and in vivo evaluation of a self-microemulsifying drug delivery
system for silybin. Journal of Chinese Pharmaceutical Sciences. 4: 342-347, 1003-1057.
22. Fraschini F, Demartini G, Esposti D., (2002). Pharmacology of silymarin. Clin Drug
Invest., 22 (1), 51-65.