Silibinin

Silibinin (INN), also known as silybin, is the major active constituent of silymarin, standardized extract of the milk thistle seeds, containing mixture of flavonolignans consisting of among others of silibinin, isosilibinin, silicristin and silidianin. Silibinin itself is mixture of two diastereomers Silibinin A and Silybinin B in approximately equimolar ratio. Both in vitro and animal research suggest that silibinin has hepatoprotective (antihepatotoxic) properties that protect liver cells against toxins. Silibinin has also demonstrated anti-cancer effects against human prostate adenocarcinoma cells, estrogen-dependent and -independent human breast carcinoma cells, human ectocervical carcinoma cells, human colon cancer cells, and both small and nonsmall human lung carcinoma cells.

Chemically modified silibinin, silibinin dihydrogen disuccinate disodium (trade name Legalon SIL) a solution for injection, is currently being tested as a treatment of severe intoxications with hepatotoxic substances, such as death cap (Amanita phalloides) poisoning. There is also clinical evidence for the use of silibinin as a supportive element in alcoholic and Child grade ‘A’ liver cirrhosis.

Pharmacology
Poor water solubility and bioavailability of silymarin led to the development of enhanced formulations. Silipide (trade name Siliphos), a complex of silymarin and phosphatidylcholine (lecithin), is about ten times more bioavailable than silymarin. It has been also reported that silymarin inclusion complex with β-cyclodextrin is much more soluble than silymarin itself. There have also been prepared glycosides of silybin, which show better water solubility and even stronger hepatoprotective effect.

Silymarin, as other flavonoids, has been shown to inhibit P-glycoprotein-mediated cellular efflux. The modulation of P-glycoprotein activity may result in altered absorption and bioavailability of drugs that are P-glycoprotein substrates. It has been reported that silymarin inhibits cytochrome P450 enzymes and an interaction with drugs primarily cleared by P450s cannot be excluded.

Toxicity
The acute toxicity of silymarin and silybin were investigated by oral and intravenous route in various animal species. No mortality or any signs of adverse effects were observed after silymarin at oral doses of 20 g/kg in mice and 1 g/kg in dogs. The median lethal dose (LD50) after intravenous infusion values are 400 mg/kg in mice, 385 mg/kg in rats and 140 mg/kg in rabbits and dogs. These data demonstrate that the acute toxicity of silymarin is very low.

Similarly, its subacute and chronic toxicity are very low; the compound is also devoid of embryotoxic potential.

Complementary and alternative medicine
A recent study suggested that silymarin may help patients with type II diabetes by assisting in blood sugar control.

Lab experiments on mice showed that Silibinin protects the hepatic cells against a-amanitin compound found in Amanita Phalloides mushroom poisoning.

Biotechnology
Silimaryn can be produced in callus and cells suspensions of Silybum marianum and substituted pyrazinecarboxamides can be used as abiotic elicitors of flavolignan production.