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http://www.medscape.com/viewarticle/422884_1

Pharmacology of Silymarin

from Clinical Drug Investigation [TM]

F. Fraschini, G. Demartini, D. Esposti,

Abstract

The flavonoid silymarin and one of its structural components,

silibinin, are substances with documented hepatoprotective

properties. Their mechanisms of action are still poorly understood.

However, the data in the literature indicate that silymarin and

silibinin act in four different ways: (i) as antioxidants, scavengers

and regulators of the intracellular content of glutathione; (ii) as

cell membrane stabilisers and permeability regulators that prevent

hepatotoxic agents from entering hepatocytes; (iii) as promoters of

ribosomal RNAsynthesis, stimulating liver regeneration; and (iv) as

inhibitors of the transformation of stellate hepatocytes into

myofibroblasts, the process responsible for the deposition of

collagen fibres leading to cirrhosis. The key mechanism that ensures

hepatoprotection appears to be free radical scavenging.

Anti-inflammatory and anticarcinogenic properties have also been

documented.

Silymarin is able to neutralise the hepatotoxicity of several agents,

including Amanita phalloides, ethanol, paracetamol (acetaminophen)

and carbon tetrachloride in animal models. The protection against A.

phalloides is inversely proportional to the time that has elapsed

since administration of the toxin. Silymarin protects against its

toxic principle -amanitin by preventing its uptake through hepatocyte

membranes and inhibiting the effects of tumour necrosis factor- ,

which exacerbates lipid peroxidation.

Clinical trials have shown that silymarin exerts hepatoprotective

effects in acute viral hepatitis, poisoning by A. phalloides, toxic

hepatitis produced by psychotropic agents and alcohol-related liver

disease, including cirrhosis, at daily doses ranging from 280 to

800mg, equivalent to 400 to 1140mg of standardised extract.

Hepatoprotection has been documented by improvement in liver function

tests; moreover, treatment with silymarin was associated with an

increase in survival in a placebo-controlled clinical trial in

alcoholic liver disease.

Pharmacokinetic studies have shown that silymarin is absorbed by the

oral route and that it distributes into the alimentary tract (liver,

stomach, intestine, pancreas). It is mainly excreted as metabolites

in the bile, and is subject to enterohepatic circulation. Toxicity is

very low, the oral 50% lethal dose being 10 000 mg/kg in rats and the

maximum tolerated dose being 300 mg/kg in dogs. Moreover, silymarin

is devoid of embryotoxic potential.

In conclusion, silymarin is a well tolerated and effective antidote

for use in hepatotoxicity produced by a number of toxins, including

A. phalloides, ethanol and psychotropic drugs. Numerous experimental

studies suggest that it acts as a free radical scavenger, with other

liver-specific properties that make it a unique hepatoprotective

agent.

[...]

6. Conclusions

The biochemical mechanism or mechanisms of the flavonoid silymarin

have not been completely established. However, the results of

numerous experimental studies strongly suggest that its

hepatoprotective effects are mainly due to free radical scavenging.

This property is reflected by the membrane stabilisation and GSH

modulation that it produces. Silymarin exerts other important

effects, which include liver-specific actions:

hepatocyte membrane stabilisation and permeability regulation,

stimulation of ribosomal RNA synthesis promoting liver regeneration,

and the prevention of the transformation of stellate hepatocytes into

myofibroblasts, which are responsible for the deposition of collagen

fibres. These properties afford effective protection against the

hepatotoxic effects of a number of xenobiotic compounds, including

Amanita phalloides toxins, ethanol and psychotropic compounds, which

has been documented in clinical trials in terms of improvement of

liver function and, in the case of ethanol, increase in survival.

Pharmacokinetic and toxicity studies have not disclosed any issues

that could limit the therapeutic use of silymarin.

In conclusion, silymarin is a well tolerated and effective antidote

for use in cases of hepatotoxicity produced by a number of

hepatotoxic agents, including Amanita phalloides, ethanol and

psychotropic drugs. Numerous experimental studies suggest that it

acts as a free radical scavenger with other liver-specific properties

that make it a unique hepatoprotective agent.