title: Induction of cytochrome P450 2E1 [corrected] promotes liver injury in ob/ob mice.
abstract: Cytochrome P450 2E1 (CYP2E1) activates several hepatotoxins and contributes to alcoholic liver damage. Obesity is a growing health problem in the United States. The aim of the present study was to evaluate whether acetone- or pyrazole-mediated induction of CYP2E1 can potentiate liver injury in obesity. CYP2E1 protein and activity were elevated in acetone- or pyrazole-treated obese and lean mice. Acetone or pyrazole induced distinct histological changes in liver and significantly higher aminotransferase enzymes in obese mice compared to obese controls or acetone- or pyrazole-treated lean mice. Higher caspase-3 activity and numerous apoptotic hepatocytes were observed in the acetone- or pyrazole-treated obese mice. Increased protein carbonyls, malondialdehyde, 4-hydroxynonenal-protein adducts, elevated levels of inducible nitric oxide synthase, and higher 3-nitrotyrosine protein adducts were found in livers of acetone- or pyrazole-treated obese animals, suggesting elevated oxidative and nitrosative stress. Liver tumor necrosis factor alpha levels were higher in pyrazole-treated animals. The CYP2E1 inhibitor chlormethiazole and iNOS inhibitor N-(3-(aminomethyl)-benzyl) acetamidine abrogated the toxicity and the oxidative/nitrosative stress elicited by the induction of CYP2E1.
  
  
  CONCLUSIONS
  These results show that obesity contributes to oxidative stress and liver injury and that induction of CYP2E1 enhances these effects.
authors.affiliation: Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Aparajita
authors.initials: A
authors.lastname: Dey
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Cederbaum
mesh_terms: D000096:Acetone; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D002384:Catalysis / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004791:Enzyme Inhibitors; D015971:Gene Expression Regulation, Enzymologic; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000150:complications* / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000235:genetics; D011506:Proteins / Q000378:metabolism; D011720:Pyrazoles; D012333:RNA, Messenger / Q000378:metabolism; D012997:Solvents; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D018736:DNA Adducts; D004791:Enzyme Inhibitors; D011506:Proteins; D011720:Pyrazoles; D012333:RNA, Messenger; D012997:Solvents; D014409:Tumor Necrosis Factor-alpha; D000096:Acetone; C002744:3-nitrotyrosine; C031280:pyrazole; D014443:Tyrosine; D019392:Cytochrome P-450 CYP2E1; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D053148:Caspase 3