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Pharmacology of Silymarin

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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 RNA synthesis, 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 α-amanitin by preventing its uptake through hepatocyte membranes and inhibiting the effects of tumour necrosis factor-α, 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.

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Acknowledgements

The authors wish to thank Madaus S.R.L., Bozen, Italy, for funding used to assist in the preparation of this manuscript.

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  1. Department of Pharmacology, University of Milan, Via Vanvitelli 32, Milan, 20129, Italy

    F. Fraschini & G. Demartini

  2. Institute of Human Physiology II, University of Milan, Milan, Italy

    D. Esposti

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Fraschini, F., Demartini, G. & Esposti, D. Pharmacology of Silymarin. Clin. Drug Investig. 22, 51–65 (2002). https://doi.org/10.2165/00044011-200222010-00007

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