Pharmacology of Silymarin

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]

(Enlarge Image)

Figure 1.

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

Silymarin is included in the pharmacopoeia of many countries under the trademark Legalon^TM or Hepatron^TM 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]

Table 1. Experimental studies on the hepatoprotective action of silymarin and silibinin in xenobiotic intoxication
Agent	Experimental model	Silymarin or silibinin action	References
Phenylhydrazine	Rat erythrocytes	Inhibition of haemolysis and lipid peroxidation	Valenzuela et al.^[22]
Rat liver	Protection from liver glutathione depletion and lipid superoxidation	Valenzuela et al.^[23]
tert-Butyl hydroperoxide	Rat microsomes Neonatal rat hepatocytes	Inhibition of O₂ consumption Reduction of enzyme loss and morphological alterations	Valenzuela & Guerra^[16] Davila et al.^[21]
	Inhibition of lipid peroxidation	Farghali et al.^[20]
Perfused rat hepatocytes
CCl4	Acute intoxication in mice and rats	Prevention of lipid peroxidation and hepatotoxicity	Letteron et al.^[31] Muriel & Mourelle^[29]
Cirrhosis in rats	Protection	Mourelle & Franco^[40];
Chronic intoxication in rats	Prevention of chronic liver damage	Mourelle et al.^[12] Muriel & Mourelle^[29] Favari & Perez Alvarex^[59]
Ethanol	Acute intoxication in rats	Neutralisation of lipid peroxidation	Valenzuela et al.^[26]
Chronic intoxication in rats	Reduction in liver alterations	Valenzuela & Garrido^[1] Campos et al.^[28] Platt & Shnorr^[32]
Halothane	Acute intoxication in rats	Protection from liver toxic effects	Siegers et al.^[11]
Thioacetamide	Acute intoxication in rats	Antihepatotoxic effects Hepatoprotection	Schriever et al.^[41]
Chronic intoxication in rats		Hahn et al.^[33]
Galactosamine	Acute hepatitis in rats	Protective effects	Barbarino et al.^[9]
Perfused rat hepatocytes	Inhibition of lipid peroxidation	Farghali et al.^[20]
Experimental hepatitis in rats	Inhibition of toxic effects on protein synthesis	Tyutyulkova et al.^[34]
Paracetamol	Acute intoxication in mice/rats	Protective effects, reduction in lipid peroxidation and glutathione depletion	Muriel et al.^[35] Campos et al.^[28]
Erythromycin estolate	Neonatal rat hepatocytes	Reduction of enzyme loss and morphological alterations	Davila et al.^[21]
Amitriptyline		Reduction of enzyme loss and morphological alterations
Nortriptyline		Reduction of enzyme loss and morphological alterations
Microcystin	Acute hepatoxicity in mice/rats	Neutralisation of lethal effects and pathological alterations	Mereish et al.^[36]

Table 1. Experimental studies on the hepatoprotective action of silymarin and silibinin in xenobiotic intoxication

Agent

Experimental model

Silymarin or silibinin action

References

Phenylhydrazine

Rat erythrocytes

Inhibition of haemolysis and lipid peroxidation

Valenzuela et al.^[22]

Rat liver

Protection from liver glutathione depletion and lipid superoxidation

Valenzuela et al.^[23]

tert-Butyl hydroperoxide

Rat microsomes
Neonatal rat hepatocytes

Inhibition of O₂ consumption Reduction of enzyme loss and morphological alterations

Valenzuela & Guerra^[16]
Davila et al.^[21]

Inhibition of lipid peroxidation

Farghali et al.^[20]

Perfused rat hepatocytes

CCl4

Acute intoxication in mice and rats

Prevention of lipid peroxidation and hepatotoxicity

Letteron et al.^[31]
Muriel & Mourelle^[29]

Cirrhosis in rats

Protection

Mourelle & Franco^[40];

Chronic intoxication in rats

Prevention of chronic liver damage

Mourelle et al.^[12]
Muriel & Mourelle^[29]
Favari & Perez Alvarex^[59]

Ethanol

Acute intoxication in rats

Neutralisation of lipid peroxidation

Valenzuela et al.^[26]

Chronic intoxication in rats

Reduction in liver alterations

Valenzuela & Garrido^[1]
Campos et al.^[28]
Platt & Shnorr^[32]

Halothane

Acute intoxication in rats

Protection from liver toxic effects

Siegers et al.^[11]

Thioacetamide

Acute intoxication in rats

Antihepatotoxic effects Hepatoprotection

Schriever et al.^[41]

Chronic intoxication in rats

Hahn et al.^[33]

Galactosamine

Acute hepatitis in rats

Protective effects

Barbarino et al.^[9]

Perfused rat hepatocytes

Inhibition of lipid peroxidation

Farghali et al.^[20]

Experimental hepatitis in rats

Inhibition of toxic effects on protein synthesis

Tyutyulkova et al.^[34]

Paracetamol

Acute intoxication in mice/rats

Protective effects, reduction in lipid peroxidation and glutathione depletion

Muriel et al.^[35]
Campos et al.^[28]

Erythromycin estolate

Neonatal rat hepatocytes

Reduction of enzyme loss and morphological alterations

Davila et al.^[21]

Amitriptyline

Reduction of enzyme loss and morphological alterations

Nortriptyline

Reduction of enzyme loss and morphological alterations

Microcystin

Acute hepatoxicity in mice/rats

Neutralisation of lethal effects and pathological alterations

Mereish et al.^[36]

Table 2. Experimental studies on the hepatoprotective action of silymarin and silibinin in fungal intoxication
Agent	Experimental model	Dose (intravenous) of silymarin or silibinin (mg/kg)	Action	References
Phalloidin, -amanitin	Acute intoxication in mice	50-150	Protection and cure	Choppin & Desplaces^[7]
Phalloidin, -amanitin	Acute intoxication in mice/rats/rabbits/dogs	15 at 60 min before phalloidin	Protection	Desplaces et al.^[6]
100 at 10 min before phalloidin	Protection
Sublethal doses of A. phalloides	Acute intoxication in dogs	50 at 5h and 30 at 24h	Prevention of increase in liver enzymes and of reduction in coagulation factors	Floersheim et al.^[45]
Phalloidin	Acute intoxication in mice	12.5-100	Protection	Vogel & Trost^[8]

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Pharmacology of Silymarin

Abstract and Introduction

Abstract

Introduction

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

Figure 1.

Figure 1.

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