Dey Aparajita, Cederbaum Arthur I
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Hepatology. 2007 Jun;45(6):1355-65. doi: 10.1002/hep.21603.
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.
These results show that obesity contributes to oxidative stress and liver injury and that induction of CYP2E1 enhances these effects.
细胞色素P450 2E1（CYP2E1）可激活多种肝毒素，并导致酒精性肝损伤。肥胖在美国是一个日益严重的健康问题。本研究的目的是评估丙酮或吡唑介导的CYP2E1诱导是否会加重肥胖状态下的肝损伤。在经丙酮或吡唑处理的肥胖和瘦小鼠中，CYP2E1蛋白和活性均升高。与肥胖对照组或经丙酮或吡唑处理的瘦小鼠相比，丙酮或吡唑在肥胖小鼠肝脏中引起了明显的组织学变化，且转氨酶水平显著更高。在经丙酮或吡唑处理的肥胖小鼠中观察到更高的半胱天冬酶-3活性和大量凋亡的肝细胞。在经丙酮或吡唑处理的肥胖动物肝脏中发现蛋白质羰基、丙二醛、4-羟基壬烯醛-蛋白质加合物增加，诱导型一氧化氮合酶水平升高，以及3-硝基酪氨酸蛋白质加合物增多，提示氧化应激和亚硝化应激增强。在经吡唑处理的动物中，肝脏肿瘤坏死因子α水平更高。CYP2E1抑制剂氯美噻唑和iNOS抑制剂N-（3-（氨基甲基）-苄基）乙脒可消除由CYP2E1诱导引起的毒性以及氧化/亚硝化应激。
这些结果表明，肥胖会导致氧化应激和肝损伤，而CYP2E1的诱导会增强这些效应。
