title: CYP2E1 potentiates toxicity in obesity and after chronic ethanol treatment.
abstract: CYP2E1 activates several hepatotoxins and contributes to alcoholic liver damage. In this report, we review our studies on whether induction of CYP2E1 can potentiate liver injury in obesity. Acetone- or pyrazole-induced severe liver injury in obese mice as compared to obese controls and lean mice. Severe liver injury was associated with elevated oxidative and nitrosative stress and could be blunted by inhibitors of CYP2E1 and inducible nitric oxide synthase (iNOS). S-Adenosyl-L-methionine (SAM) lowered the elevated oxidative and nitrosative stress, steatosis, liver injury and mitochondrial dysfunction in the pyrazole-treated obese mice. The protection by SAM may have therapeutic applications against metabolic complications caused by obesity. The role of CYP2E1 in chronic ethanol-induced liver injury was studied using wild-type (WT) mice, CYP2E1 knockout (KO) mice and humanized CYP2E1 knockin (KI) mice. Ethanol produced fatty liver and oxidant stress in WT mice; these effects were blunted in the CYP2E1 KO mice but restored in the CYP2E1 KI mice. Significant liver injury was produced in the ethanol-fed KI mice in association with elevated oxidant stress and levels of human CYP2E1. Collectively, these studies show that CYP2E1 contributes to ethanol-induced and obesity-induced oxidant stress and liver injury.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY, USA. arthur.cederbaum@mssm.edu
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Cederbaum
mesh_terms: D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D008107:Liver Diseases / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications*; D018384:Oxidative Stress; D012436:S-Adenosylmethionine / Q000494:pharmacology
chemical_list: D000431:Ethanol; D012436:S-Adenosylmethionine; D019392:Cytochrome P-450 CYP2E1