Silymarin as a New Hepatoprotective Agent in Experimental Cholestasis: New Possibilities for an Ancient Medication

Abstract

Silymarin is a purified extract from milk thistle (Silybum marianun (L.) Gaertn), composed of a mixture of four isomeric flavonolignans: silibinin (its main, active component), isosilibinin, silydianin and silychristin. This extract has been empirically used as a remedy for almost 2000 years, and remains being used as a medicine for many types of acute and chronic liver diseases. Despite its routinely clinical use as hepatoprotectant, the mechanisms underlying its beneficial effects remain largely unknown. This review addresses in detail a number of recent studies showing a novel feature of silymarin as a hepatoprotective drug, namely: its anticholestatic properties in experimental models of hepatocellular cholestasis with clinical correlate. For this purpose, this review will cover the following aspects: 1. The chemistry of silymarin, including chemical composition and properties. 2. The current clinical applications of silymarin as a hepatoprotective agent, including the mechanisms by which silymarin is thought to exert its hepatoprotective properties, when known. 3. The physiological events involved in bile formation, and the mechanisms of hepatocellular cholestasis, focusing on cellular targets and mechanisms of action of drugs used to reproduce experimentally cholestatic diseases of clinical interest, in particular estrogens and monohydroxylated bile salts, where anticholestatic properties of silymarin have been tested so far. 4. The recent findings describing the impact of silymarin on normal bile secretion and its novel, anticholestatic properties in experimental models of cholestasis, with particular emphasis on the cellular/molecular mechanisms involved, including modulation of bile salt synthesis, biotransformation/depuration of cholestatic compounds, changes in transporter expression/activity, and evocation of signaling pathways.

Silymarin Reduces Profibrogenic Cytokines and Reverses Hepatic Fibrosis in Chronic Murine Schistosomiasis

“…It prevents apoptotic and necrotic cell death in the liver (31) and retards the progression of alcohol-induced hepatic fibrosis (32). Silymarin is the natural product of most widespread use in the treatment of liver diseases (33), and it is sold over the counter all over the world (34). Its low toxicity encouraged researchers to use silymarin in long-term tests in chronic and severe liver conditions in humans, and its efficacy in the prevention of liver fibrosis and stimulation of liver regeneration was observed in alcoholic and nonalcoholic fatty liver diseases and in drug-and chemical-induced hepatic toxicity (35).…”

Biliary Sludge: Can we Avoid Punishing Gallbladder by Srivastava Regimen of Integrated Approach of Medicine?

“…One of the best studied cholagogues is silymarin from milk thistle Silybum marianum, which is mixture of four isomeric flavonolignans; silibinin (most active component), isosilibinin, silydianin and silychristin. 18 Silymarin induces hepatic output of bile acids and bile acid-dependent choleresis, but does not affect bile acid-independent bile flow.…”

Pharmacokinetics and Metabolic Profile of Free, Conjugated, and Total Silymarin Flavonolignans in Human Plasma after Oral Administration of Milk Thistle Extract

“…Silymarin is also used for the treatment of Amanita phalloides mushroom poisoning (Desplaces et al, 1975;Hruby et al, 1983;Vogel et al, 1984). In vitro and animal studies have demonstrated the hepatoprotective properties of silymarin or silybin (a mixture of SB A and SB B ) (Fraschini et al, 2002;Hoofnagle, 2005;Crocenzi and Roma, 2006). Several clinical trials have shown an excellent safety profile for silymarin in humans (Fraschini et al, 2002;Ball and Kowdley, 2005;Dryden et al, 2006).…”