Guest guest Posted April 17, 2000 Report Share Posted April 17, 2000 Mechanism of Action Silymarin has been reported to protect liver cells from a wide variety of toxins, including acetaminophen, ethanol, carbon tetra-chloride, and D-galactosamine.18-23 Silymarin has also been found to protect liver cells from ischemic injury,24 radiation,25 iron toxicity,26 and viral hepatitis.27 The mechanisms which provide silymarin's hepatoprotective effects are many and varied, and include antioxidation,21,26,28 anti-lipid peroxidation,19,28,29 enhanced detoxification,30-32 and protection against glutathione depletion.33,23 Silymarin has been found to inhibit the formation of leukotrienes from polyunsaturated fatty acids in the liver, via its inhibition of the enzyme lipoxygenase. These leukotrienes are known to be some of the most damaging chemicals found in man.34 Studies also demonstrated that silymarin increased hepatocyte protein synthesis,35,36 decreased the activity of tumor promo-ters,37 stabilized mast cells,38 modulated immune functions,39,40 and was anti-inflam- matory41-43 and antifibrotic.44-46 Stimulation of Liver Regeneration: One of the mechanisms to explain the ability of silymarin to stimulate the regeneration of hepatic tissue is the increase in protein synthesis in damaged livers. In both in vivo and in vitro experiments, significant increases in the formation of ribosomes and DNA synthesis were measured in addition to the increase in protein synthesis. Interestingly, the increased protein synthesis was only measured in damaged livers (partial hepectomy), not in controls.35 The mechanism of increased protein synthesis is currently not known but some authors speculate silymarin imitates a physiologic regulator, so the silybin fits into a specific binding site on the polymerase, thus stimulating ribosome formation.36 The potential for stimulation of protein synthesis by silymarin was investigated in malignant liver tissue, and no increases in protein synthesis, ribosome formation, or DNA synthesis were found in malignant cell lines.35 Anti-inflammatory Effects: The mainstays of the current medical management of nonviral chronic hepatitis are immunosuppressive/anti-inflammatory medications (e.g., prednisone, azathioprine). While use of these drugs may be lifesaving, long-term use may result in debilitating, life-threatening side-effects. Doctors and patients need safe and effective alternative anti-inflammatory medications. Botanical anti-inflammatories may constitute such a group. Silymarin has been shown to have significant anti-inflammatory effects on hepatic tissue. Several studies have demonstrated a variety of anti-inflammatory effects, including mast cell stabilization,38 inhibition of neutrophil migration,47 Kuppfer cell inhibition,43 strong inhibition of leukotriene synthesis, and prostaglandin formation.41-43 Antifibrotic Effects: Hepatic stellate cells play a central pathogenic role in liver fibrogenesis. In response to some fibrotic influences (e.g., chronic ethanol exposure, carbon tetrachloride, etc.), they proliferate and transform into myofibroblasts, which are responsible for the deposition of collagen fibers in the liver. One recent study investigated the effect of silybin on the transformation of hepatic stellate cells into myofibroblasts. Silybin [10-4 mol/l concentration] was found to reduce the proliferation of freshly isolated rat hepatic stellate cells by about 75 percent. It also reduced the conversion of stellate cells into myofibroblasts and down-regulated the gene expression of extracellular matrix components necessary for fibrosis.44 Silymarin has been shown to slow or reverse liver fibrosis in animals. Rats were subjected to a complete bile duct occlusion which consistently causes progressive liver fibrosis without inflammation. Silymarin was able to reduce the fibrosis by 30-35 percent in comparison with controls (50 mg/kg/day, human dose = 3500 mg/day). Silymarin worked equally if used continuously for six weeks after the bile duct occlusion or only for the final two weeks. Dosage at 25 mg/kg/day (human dose = 1750 mg/day) was not found to be effective.45 Colchicine is currently used to inhibit fibrosis of the liver. It functions as an antifibrotic and anti-inflammatory by inhibiting macrophage stimulation of fibrosis. Unfortunately, colchicine has a narrow, unpredictable therapeutic window, and serious, life-threatening side-effects, including liver failure, renal failure, myocardial injury, severe gastrointestinal damage, shock, and death. In a rat study using carbon tetrachloride-induced liver fibrosis, silymarin was found to be very similar to colchicine for the prevention of chronic liver fibrosis, but without any side-effects.46 Inhibition of P450: Paradoxically, silymarin may have an inhibitory effect on the cytochrome P450 (Phase I) detoxification system. In a recently published animal study, silybin was found to inhibit several specific induced P450 enzymes in mice.30 Other researchers have noted the lack of stimulatory effect on the P450 detoxification system.29,31 This effect may explain some of the hepatoprotective effects of silymarin, especially against Amanita poisoning. Amanitin toxin becomes deadly to hepatocytes only after it becomes bioactivated by the P450 system. The inhibition of the bioactivation of amanitin could reduce its toxic effects. In addition, silymarin and other antioxidants afford some protection against the free radicals generated by P450 enzymes.48 Enhanced Glucuronidation: Gluc-uronidation is an important Phase II liver detoxification pathway. More toxins are removed from the body via glucuronidation than any other single detoxification pathway.48 Glucuronic acid is conjugated with toxins to facilitate their elimination from the body via the bile. In addition, many other substances, including estrogen, are removed from the body via glucuronidation. Unfortunately, some intestinal bacteria (mostly pathogenic) possess an enzyme, beta-glucuronidase, that enables them to remove glucuronic acid from the conjugated substance and use it as an energy source. This allows the original molecule to be reabsorbed through the GI mucosa, thus re-exposing the person to the removed substance. Silymarin was found to inhibit the activity of beta-glucuronidase 53 percent in healthy humans and in one patient with colon cancer.32 Immunomodulation: Researchers have investigated the immunomodulatory effects of silymarin on the diseased liver. A pair of Hungarian studies demonstrated a positive effect of silymarin on immune function. The first study looked at patients with histologically proven chronic alcoholic liver disease. These patients originally had low T-cell percentage, high CD8+ cell percentage, and an enhanced antibody-dependent increase in lymphocyte cytotoxicity. All of these abnormal immune findings were normalized by a six-month course of silymarin. No significant changes were found after six months in the control group.39 The second study looked at the hepatoprotective effect of silymarin in addition to its effects on normalizing immune function. Forty patients with alcoholic cirrhosis of the liver were given either silymarin, amino-imidazole-carboxamide-phosphate, or placebo in a one-month, double-blind clinical trial. In the treated groups, silymarin normalized elevated levels of AST, ALT, and total bilirubin, markedly reduced the high level of GGT, decreased the percentage of OKT8+ cells, and suppressed lymphocytotoxicity.40 Dosage/Toxicity Silybum marianum is not water soluble and is typically administered as an encapsulated standardized extract (70-80% silymarin). In animals, silymarin has proven to be non-toxic when administered at high doses for short periods of time and long term dosage in rats has also failed to demonstrate any toxicity. Human studies have shown silymarin to be generally without side-effects. The typical adult dosage for silymarin is 240-900 mg/day in two or three divided doses. At higer doses (>1500 mg/day) silymarin may produce a laxative effect due to increased bile flow and secretion. Mild allergic reactions have also been noted, but neither of these side-effects was severe enough to discontinue treatment.49-51 ______________________________________________________ Get Your Private, Free Email at http://www.hotmail.com Quote Link to comment Share on other sites More sharing options...
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