Adenovirus-mediated expression of CYP2E1 produces liver toxicity in mice
Adenovirus-mediated expression of CYP2E1 produces liver toxicity in mice
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DOI：
10.1093/toxsci/kfj165
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发表时间：
2006-06-01
影响因子：
3.8
通讯作者：
Cederbaum, Arthur I.
中科院分区：
文献类型：
--
作者：
Bai, Jingxiang;Cederbaum, Arthur I.
乙醇诱导细胞色素P450 2 E1被认为是乙醇产生氧化应激状态并导致肝毒性的中心途径之一。为了研究CYP 2 E1的生化和毒理作用及其对肝损伤的增敏作用，构建了一种能介导CYP 2 E1过表达的腺病毒。通过尾静脉将该病毒注射到小鼠体内，与注射Ad-LacZ或生理盐水的小鼠相比，小鼠肝脏中的CYP 2 E1蛋白和活性升高两倍。在注射CYP 2 E1腺病毒的小鼠中，转氨酶水平显著升高。注射Ad-2 E1的小鼠的肝脏标本的组织学评价显示肝细胞损伤。末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记（TUNEL）法显示，Ad-2 E1感染组小鼠肝脏中阳性细胞数明显多于Ad-LacZ感染组。3-与Ad-LacZ相比，Ad-2 E1感染小鼠肝脏中的硝基酪氨酸蛋白加合物和蛋白羰基加合物增加。这种增强的毒性很可能反映了CYP 2 E1和腺病毒介导的毒性途径之间的相互作用。这些结果表明，腺病毒介导的CYP 2 E1过表达可诱导小鼠肝毒性，并提示其机制涉及氧化/亚硝化应激。
Induction of cytochrome P450 2E1 by ethanol is believed to be one of the central pathways by which ethanol generates a state of oxidative stress and causes hepatotoxicity. In order to evaluate the biochemical and toxicological actions of CYP2E1 and its sensitization of hepatotoxin-induced injury, an adenovirus which can mediate overexpression of CYP2E1 was constructed. Injecting this virus into mice through the tail vein elevated CYP2E1 protein and activity twofold in the liver of the mice compared with the mice injected with Ad-LacZ or saline. Transaminase levels were dramatically increased in mice injected with the CYP2E1 adenovirus. Histological evaluation of liver specimens of mice injected with Ad-2E1 showed liver cell injury. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay demonstrated that more cells were stained positively in the liver of the mice infected with Ad-2E1 than in the liver of the mice infected with Ad-LacZ. 3-Nitrotyrosine protein adducts and protein carbonyl adducts were increased in the liver of the mice infected with Ad-2E1 compared with Ad-LacZ. This potentiated toxicity most likely reflects interactions between CYP2E1- and adenovirus-mediated toxicity pathways. These results show that adenovirus-mediated overexpression of CYP2E1 could induce liver toxicity in mice and suggests a mechanism involving oxidative/nitrosative stress.