[Silibinin and its hepatoprotective action from the perspective of a toxicologist]. / Sylibinina i jej dzialanie hepatoprotekcyjne z punktu widzenia toksykologa.

Silibinin is the most active component of a complex of flavonoids -silymarin contained in fruit milk thistle (Sylibum marianum). Its mechanism of action is complex and highly beneficial in protecting hepatocytes. On the one hand this compound blocks the penetration of various toxins (for example amanitin) into the hepatocytes not allowing in this way for the cell death and on the other hand, it prevents apoptosis through intracellular. It protects the liver from oxidative intracellular free radicals by increasing the activity of enzyme superoxide dismutase and peroxidase, as well as by increasing the concentration of glutathione and the activity of the peroxidase. Silibinin strengthens and stabilizes the cell membranes, inhibits the synthesis of prostaglandins associated with the lipid peroxidation and promotes regeneration of liver through the stimulation of protein synthesis and effect on the production of new hepatocytes. A particularly interesting topic from the perspective of a toxicologist is the application of silibinin in Amanita phalloides poisoning. Clinical trials conducted in this respect are very encouraging. The other beneficial application of silibinin is in therapy of the alcoholic liver cirrhosis. The evidence shows that the use of silymarin leads to a significant reduction in liver-related mortality and even reduction in the number of patients with encephalopathy in the course of the disease. Application of silibinin goes beyond liver disease and expands in the direction of cancer and even diabetes. What is interesting is the fact, that the substance of herbal origin occurring in the environment is so strong, favorable, beneficial and multidirectional. Science has contributed to improving the bioavailability of silibinin thus making it more effective.

Failure of N-acetylcysteine to reduce alpha amanitin toxicity.

Acetaminophen undergoes toxic conversion in the liver to a free-radical intermediary which binds to glutathione. N-Acetylcysteine acts as a glutathione precursor when natural stores are depleted, and is an effective antidote for acetaminophen overdose. Mushrooms containing amatoxins (such as Amanita phalloides) may undergo similar toxic conversion. However, in our amatoxin-poisoned mouse model, N-acetylcysteine (1.2 g kg-1) produced no change in survival or hepatic enzyme elevation compared to control animals. We conclude that N-acetylcysteine has no clinical role in the treatment of Amanita phalloides ingestion.

Anti-phalloidine and anti-alpha-amanitine action of silybin in comparison with compounds similar to structural parts of silybin.

Silybin significantly antagonises the lethal poisoning of mice with alpha-amanitine or phalloidine. In the same test, taxifolin, coniferyl alcohol, fisetin and (+)-catechin were not effective.

On the nephrotoxicity of alpha-amanitin and the antagonistic effects of silymarin in rats.

In human beings, poisoning by the deathcup mushroom causes renal lesions in addition to extremely severe liver damage. It is known from animal experiments that silymarin, a polyhydroxyphenylchromanone, is capable of counteracting this alpha-amanitin-induced liver damage. The purpose of the present work was to ascertain whether renal damage could be induced in rats by giving alpha-amanitin, and whether silymarin would have any effect on such renal damage. The fact that alpha-amanitin produces pathological changes in the kidneys and that these lesions can be almost completely prevented by pretreating rats with silymarin has now been amply demonstrated by biochemical and histological techniques alike.

alpha-Amanitin: inactivation by bovine lactoperoxidase.

The principle amatoxin, alpha-amanitin, is found to be extremely sensitive toward lactoperoxidase catalyzed degradation, rather than iodination, of the indole nucleus. Extensive attenuation of inhibitor potency against eukaryotic DNA-dependent RNA polymerase II accompanies the treatment of alpha-amanitin with lactoperoxidase, iodide and hydrogen peroxide.

The action of silybin on the mouse liver in alpha-amanitine poisoning.

Histochemical and histoenzymological studies were carried out on liver slices from mice which had received alpha-amanitine two days previously, some of which had been treated with silybin, and from control mice. The toxin produced certain changes in the activity of the enzymes involved in different metabolic processes, and in the amounts of lipids and nucleic acids. Treatment with silybin, given 60 min before administering alpha-amanitine or 10 min later alike, prevents the appearance of these changes and gives results comparable to those in the control animals.

Recovery of amnestic effect of alpha-amanitin by post-training administration of d-amphetamine in the rat.

alpha-Amanitin, an inhibitor of RNA polymerase II, given intraventricularly 6 or 24 h before training, impaired consolidation of both passive and active avoidance responses in rats. Administration of d-amphetamine sulfate (0.5 mg/kg intraperitoneally) immediately after training produced a clear-cut antiamnestic effect in alpha-amanitin-injected rats without modifying consolidation in control animals. Examination of several parameters of conditioning enabled the authors to rule out an impairment in locomotor performance of alpha-amanitin-treated rats both in training and in test sessions. The amnestic effect of alpha-amanitin and recovery by means of d-amphetamine were discussed in relation to RNA synthesis inhibition and a possible restoring effect of d-amphetamine upon alpha-amanitin-induced decrease of brain RNA content.