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LIVER AND BILIARY TRACT

Opposite action of S-adenosyl methionine and its metabolites on CYP2E1-mediated toxicity in pyrazole-induced rat hepatocytes and HepG2 E47 cells

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York

Submitted 31 August 2005 ; accepted in final form 20 November 2005

S-adenosyl-L-methionine (SAMe) is protective against a variety of hepatotoxins, including ethanol. The ability of SAMe to protect against cytochrome P-450 2E1 (CYP2E1)-dependent toxicity was studied in hepatocytes from pyrazole-treated rats and HepG2 E47 cells, both of which actively express CYP2E1. Toxicity was initiated by the addition of arachidonic acid (AA) or by depletion of glutathione after treatment with L-buthionine sulfoximine (BSO). In pyrazole hepatocytes, SAMe (0.25–1 mM) protected against AA but not BSO toxicity. SAMe elevated GSH levels, thus preventing the decline in GSH caused by AA, and SAMe prevented AA-induced lipid peroxidation. SAMe analogs such as methionine or S-adenosyl homocysteine, which elevate GSH, also protected against AA toxicity. 5'-Methylthioadenosine (MTA), which cannot produce GSH, did not protect. The toxicity of BSO was not prevented by SAMe and the analogs because GSH cannot be synthesized. In contrast, in E47 cells, SAMe and MTA but not methionine or S-adenosyl homocysteine potentiated AA and BSO toxicity. Antioxidants such as trolox or N-acetyl cysteine prevented this synergistic toxicity of SAMe plus AA or SAMe plus BSO, respectively. In pyrazole hepatocytes, SAMe prevented the decline in mitochondrial membrane potential produced by AA, whereas in E47 cells, SAMe potentiated the decline in mitochondrial membrane potential. In E47 cells, but not pyrazole hepatocytes, the combination of SAMe plus BSO lowered levels of the antioxidant transcription factor Nrf2. Because SAMe can be metabolized enzymatically or spontaneously to MTA, MTA may play a role in the potentiation of AA and BSO toxicity by SAMe, but the exact mechanisms require further investigation. In conclusion, contrasting effects of SAMe on CYP2E1 toxicity were observed in pyrazole hepatocytes and E47 cells. In hepatocytes, SAMe protects against CYP2E1 toxicity by a mechanism involving maintaining or elevating GSH levels.

S-adenosyl-L-methionine; cytochrome P-450 2E1; hepatotoxicity; oxidative stress