S-adenosyl methionine protects ob/ob mice from CYP2E1-mediated liver injury.
Pyrazole treatment to induce cytochrome P-450 2E1 (CYP2E1) was recently shown to cause liver injury in ob/ob mice but not in lean mice. The present study investigated the effects of S-adenosyl-l-methionine (SAM) on the CYP2E1-dependent liver injury in ob/ob mice. Pyrazole treatment of ob/ob mice for 2 days caused necrosis, steatosis, and elevated serum transaminase and triglyceride levels compared with saline ob/ob mice. Administration of SAM (50 mg/kg body wt ip every 12 h for 3 days) prevented the observed pathological changes as well as the increase of apoptotic hepatocytes, caspase 3 activity, and serum TNF-alpha levels. SAM administration inhibited CYP2E1 activity but not CYP2E1 content. The pyrazole treatment increased lipid peroxidation, 4-hydroxynonenal and 3-nitrotyrosine protein adducts, and protein carbonyls. These increases in oxidative and nitrosative stress were prevented by SAM. Treatment of ob/ob mice with pyrazole lowered the endogenous SAM levels, and these were elevated after SAM administration. Mitochondrial GSH levels were very low after pyrazole treatment of the ob/ob mice; this was associated with elevated levels of malondialdehyde and 4-hydroxynonenal and 3-nitrotyrosine protein adducts in the mitochondria. All these changes were prevented with SAM administration. SAM protected against pyrazole-induced increase in serum transaminases, necrosis, triglyceride levels, caspase-3 activity, and lipid peroxidation even when administered 1 day after pyrazole treatment. In the absence of pyrazole, SAM lowered the slightly elevated serum transaminases, triglyceride levels, caspase-3 activity, and lipid peroxidation in obese mice. In conclusion, SAM protects against and can also reverse or correct CYP2E1-induced liver damage in ob/ob mice.
Dey
Aparajita
A
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Caro
Andres A
AA
Cederbaum
Arthur I
AI
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D019392:Cytochrome P-450 CYP2E1 / Q000633:toxicity*; D053938:DNA Fragmentation / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008107:Liver Diseases / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008930:Mitochondria, Liver / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects; D011720:Pyrazoles; D012436:S-Adenosylmethionine / Q000494:pharmacology*
D011720:Pyrazoles; C031280:pyrazole; D012436:S-Adenosylmethionine; D019392:Cytochrome P-450 CYP2E1; D052247:Nitric Oxide Synthase Type II