Induction of cytochrome P450 2E1 [corrected] promotes liver injury in ob/ob mice.
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.
Dey
Aparajita
A
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Cederbaum
Arthur I
AI
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
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