Protective effects of silymarin against photocarcinogenesis in a mouse skin model.
Katiyar SK; Korman NJ; Mukhtar H; Agarwal R
Department of Dermatology, Case Western Reserve University, Cleveland, OH 44106, USA.
J Natl Cancer Inst (UNITED STATES) Apr 16 1997, 89 (8) p556-66
BACKGROUND: Nonmelanoma skin cancer is the most common cancer among humans; solar UV is its major cause. Therefore, it is important to identify agents that can offer protection against this cancer. PURPOSE: We evaluated the protective effects of silymarin, a flavonoid compound isolated from the milk thistle plant, against UVB radiation-induced nonmelanoma skin cancer in mice ad delineated the mechanism(s) of its action. METHODS: For long-term studies, three different protocols of treatment were employed, each evaluating protection by silymarin at a different stage of carcinogenesis. Female SKH-1 hairless mice were subjected to 1) UVB-induced tumor initiation followed by phorbol ester-mediated tumor promotion, 2) 7,12-dimethylbenz[a]anthracene-induced tumor initiation followed by UVB-mediated tumor promotion, and 3) UVB-induced complete carcinogenesis. Forty mice were used in each protocol and were divided into control and treatment groups. Silymarin was applied topically at a dose of 9 mg per application before UVB exposure, and its effects on tumor incidence (% of mice with tumors), tumor multiplicity (number of tumors per mouse), and average tumor volume per mouse were evaluated. In short-term studies, the following parameters were measured: formation of sunburn and apoptotic cells, skin edema, epidermal catalase and cyclooxygenase (COX) activities, and enzymatic activity and messenger RNA (mRNA) expression for ornithine decarboxylase (ODC), a frequently observed marker at tumor promotion stage. Fisher's exact test was used to evaluate differences in tumor incidence, two-sample Wilcoxon rank sum test was used for tumor multiplicity and tumor volume, and Student's t test was used for all other measurements. All statistical tests were two-sided. RESULTS: In the protocol with UVB-induced tumor initiation, silymarin treatment reduced tumor incidence from 40% to 20% (P = .30), tumor multiplicity by 67% (P = .10), and tumor volume per mouse by 66% (P = .14). In the protocol with UVB-induced tumor promotion, silymarin treatment reduced tumor incidence from 100% to 60% (P<.003), tumor multiplicity by 78% (P<.0001), and tumor volume per mouse by 90% (P<.003). The effect of silymarin was much more profound in the protocol with UVB-induced complete carcinogenesis, where tumor incidence was reduced from 100% to 25% (P<.0001), tumor multiplicity by 92% (P<.0001), and tumor volume per mouse by 97% (P<.0001). In short-term experiments, silymarin application resulted in statistically significant inhibition in UVB-caused sunburn and apoptotic cell formation, skin edema, depletion of catalase activity, and induction of COX and ODC activities and ODC mRNA expression. CONCLUSIONS AND IMPLICATION: Silymarin can provide substantial protection against different stages of UVB-induced carcinogenesis, possibly via its strong antioxidant properties. Clinical testing of its usefulness is warranted.
Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients
Journal of Hepatology (Denmark), 1997, 26/4 (871-879)
Background/Aims: Several studies have demonstrated that diabetic patients with cirrhosis require insulin treatment because of insulin resistance. As chronic alcoholic liver damage is partly due to the lipoperoxidation of hepatic cell membranes, anti-oxidizing agents may be useful in treating or preventing damage due to free radicals. The aim of this study was to ascertain whether long-term treatment with silymarin is effective in reducing lipoperoxidation and insulin resistance in diabetic patients with cirrhosis. Methods: A 12-month open, controlled study was conducted in two well-matched groups of insulin-treated diabetics with alcoholic cirrhosis. One group (n = 30) received 600 mg silymarin per day plus standard therapy, while the control group (n = 30) received standard therapy alone. The efficacy parameters, measured regularly during the study, included fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria levels, glycosylated hemoglobin (HbA1c) and malondialdehyde levels. Results: There was a significant decrease (p < 0.01) in fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria and HbA1c levels already after 4 months of treatment in the silymarin group. In addition, there was a significant decrease (p < 0.01) in fasting insulin levels and mean exogenous insulin requirements in the treated group, while the untreated group showed a significant increase (p < 0.05) in fasting insulin levels and a stabilized insulin need. These findings are consistent with the significant decrease (p < 0.01) in basal and glucagon-stimulated C-peptide levels in the treated group and the significant increase in both parameters in the control group. Another interesting finding was the significant decrease (p < 0.01) in malondialdehyde/levels observed in the treated group. Conclusions: These results show that treatment with silymarin may reduce the lipoperoxidation of cell membranes and insulin resistance, significantly decreasing endogenous insulin overproduction and the need for exogenous insulin administration.
Comparative effects of colchicine and silymarin on CCl4-chronic liver damage in rats
Archives of Medical Research (Mexico), 1997, 28/1 (11-17)
The comparative effects of colchicine (10 microg day-1, p.o.) and silymarin (50 mg kg-1, p.o.) each given for 5 days a week on the chronic carbon tetrachloride (CCl4) liver damage were studied. Treatment with CCl4 resulted in a marked reduction of Na+, K+, and Ca2+-ATPases in plasma liver membranes as compared to vehicles or either silymarin or colchicine alone. Collagen content in livers of animals treated with CCl4 was increased about four-fold as compared to controls and histological examination of liver samples showed that collagen increase distorted the normal liver architechture. Colchicine or silymarin treatment completely prevented all the changes observed in CCl4-cirrhotic rats (namely, lipid peroxidation, Na+, K+ and Ca2+-ATPases), except for liver collagen content which was reduced only 55% as compared with CCl4-treated rats and for alkaline phosphatase and glutamic pyruvic transaminase which still remained above controls. In the CCl4 + silymarin group, the loss of glycogen content was completely prevented. However, when rats were treated with CCl4 + colchicine, liver glycogen content could not be restored. The hepatoprotective effects of colchicine or silymarin were very similar in regard tea the prevention of chronic liver damage.
Properties and medical use of flavonolignans (Silymarin) from Silybum marianum
Phytotherapy Research (United Kingdom), 1996, 10/SUPPL. 1 (S25-S26)
Purified flavonolignan extracts from the fruits of the milk thistle (Silybum marianum (L.) Gaertn., syn. Carduus marianus L.) mainly contain silymarin, an isomer mixture of silibinin, isosilibinin, silicristin and silidianin. Silymarin is used for oral treatment of toxic liver damage (induced by alcohol, drugs or environmental toxins) and for supportive therapy in chronic inflammatory liver diseases and in liver cirrhosis. Silymarin and its main isomer silibinin, respectively, have been shown to possess antioxidant properties thus preventing lipid peroxidation and membrane destruction in cells. In addition, protein biosynthesis and cell regeneration are accelerated in the damaged liver leading to restoration of the liver functions. Certain mushroom toxins are prevented from entering the liver cell by silibinin due to competitive inhibition of receptors at the cell membrane. Intravenous treatment with a soluble silibinin derivative is now an important life-saving factor in the standard therapy of cases of Amanita phalloides poisoning. Finally, it has recently been shown that silymarin inhibits leukotriene production which explains its antiinflammatory effect and that it has an antifibrotic action. Clinical trials confirm the positive effects found in experimental studies. Thus, silymarin is nowadays not only the best documented drug for liver therapy but also one of the most intensively investigated plant extracts with known mechanisms of action.
Reliable phytotherapy in chronic liver diseases
Therapiewoche (Germany), 1996, 46/17 (916+918-919)
More than 2.5 million people in Germany suffer from chronic liver disease, most of them of alcoholic origin. Silymarin, extracted from silver thistle (Silybum marianum), was proved to develop antitoxic and antifibrotic effects in experimental as well as in human toxic liver damage. Long term treatment is able to reduce mortality even in patients with established alcoholic liver cirrhosis. However only a qualified preparation with adequate liberation of silymarin should be used because of the great differences in bioavailability of various products, as shown recently. According to the data available today, silymarin treatment should be applied to all patients suffering from alcoholic liver disease because of its possible favourable effects on prognosis.
Prevention of CCL4-induced liver cirrhosis by silymarin.
Fundam Clin Pharmacol (1989) 3(3):183-91
The efficacy of silymarin treatment in preventing biochemical and histological alterations in CCL4-induced liver cirrhosis in rats was studied. Four groups of rats were treated with: (1) CCL4; (2) mineral oil; (3) CCL4 + silymarin; and (4) silymarin. All animals were sacrificed 72 h after the end of treatments. The activities of alkaline phosphatase (alk. phosp.), gamma-glutamyl transpeptidase (GGTP), glutamic pyruvic transaminase (GPT) and glucose-6-phosphatase (G6Pase), and bilirubin content were determined in serum. Na+, K+- ATPase and Ca++-ATPase activities were measured in isolated plasma membranes. Lipoperoxidation, triglycerides (TG), and glycogen contents were also measured in liver homogenates. Liver cirrhosis was evidenced by significant increases in liver collagen, lipoperoxidation, serum activities of alk. phosp., GGTP, GPT, G6Pase, bilirubin content, and liver TG. Activities of ATPases determined in plasma membranes were significantly reduced, as was liver glycogen content. Silymarin cotreatment (50 mg/kg b.wt) completely prevented all the changes observed in CCL4-cirrhotic rats, except for liver collagen content which was reduced only 30% as compared to CCL4- cirrhotic rats. Silymarin protection can be attributed to the agent's antioxidant and membrane-stabilizing actions.
Free radicals in tissue damage in liver diseases and therapeutic approach.
Tokai J Exp Clin Med (1986) 11 Suppl:121-34
In vitro and in vivo effects of four hepatoprotective agents: silymarin (LegalonR),(+)-cyanidanol-3 (CatergenR), 6,6-methylene-bis (2,2,4-trimethyl-1, 2-dihydroquinoline) (MTDQ), and 4,5-amino- imidazole-carboxamide-phosphate (Aica-P) on the expression and activity of superoxide dismutase enzyme and on certain cellular immune reactions were studied in lymphocytes (and erythrocytes) from cirrhotic patients and from healthy control subjects. In vitro incubation with these drugs inhibited lectin-induced lymphocyte transformation and some of them decreased the antibody-dependent, spontaneous, and lectin-induced lymphocytotoxicity. MTDQ, silymarin and Aica-P enhanced the superoxide dismutase activity of erythrocytes and lymphocytes and the two latter and (+)-cyanidanol-3 increased the superoxide expression of lymphocytes as measured by flow cytofluorometry. In vivo treatment with Aica-P restored the originally low lymphocyte transformation values of patients' lymphocytes. Our results indirectly suggest that both antioxidant and immunomodulatory activities might be important factors in the hepatoprotective action of these drugs.