Pharmacology of Silymarin

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

Disclosures

Clin Drug Invest. 2002;22(1) 

In This Article

Abstract and Introduction

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.

Introduction

Flavonoids belong to the family of the benzo gamma-pyrones. More than 4000 different flavonoids are currently known; they are ubiquitous not only in the plant kingdom, where they are particularly abundant in the photosynthetic cells of higher plants, but also in the animal kingdom. For centuries they have been attributed numerous therapeutic properties and many have been used as popular therapeutic remedies. Compounds such as quercetin, taxifolin and silymarin have been used as active ingredients, both alone and as components of complex chemical preparations.

Silymarin is a flavonolignan that has been introduced fairly recently as a hepatoprotective agent. It is the most well known compound of the flavonoids, thanks to its well defined therapeutic properties. It is extracted from the seeds and fruit of Silybum marianum (Compositae) and in reality is a mixture of three structural components: silibinin, silydianine and silychristine. The structure of the constituents of silymarin was clarified in the 1960s (figure 1).[1,2]

The main chemical difference between silymarin and other flavonoids is that its isomers are substituted by a coniferyl alcohol group. Of the three isomers that constitute silymarin, silibinin is the most active.[3,4] From a medical point of view, silymarin and silibinin have been found to provide cytoprotection and, above all, hepatoprotection.[2,5]

Silymarin is used for the treatment of numerous liver disorders characterised by degenerative necrosis and functional impairment.[3] Furthermore, it is able to antagonise the toxin of Amanita phalloides[6,7] and provides hepatoprotection against poisoning by phalloidin,[8] galactosamine,[9] thioacetamide,[10] halothane[11] and carbon tetrachloride.[12] The compound also protects hepatocytes from injury caused by ischaemia, radiation, iron overload and viral hepatitis.[13]

Figure 1.

The three structural components of silymarin: silibinin, silydianine, and silychristine.

Silymarin is included in the pharmacopoeia of many countries under the trademark LegalonTM or HepatronTM and is often used as supportive therapy in food poisoning due to fungi and in chronic liver disorders, such as steatosis[14] and alcohol-related liver disease.[15]

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