Overexpression of CYP2E1 and Alcohol Liver Disease

CYP2E1 过度表达与酒精性肝病

• 批准号: 7094241
• 负责人: JINGXIANG BAI
• 金额: $ 8.28万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094241
• 关键词: alcoholic beverage consumption; antioxidants; chemoprevention; cytochrome P450; cytokine; cytoprotection; enzyme activity; enzyme inhibitors; enzyme mechanism; ethanol; glutathione; hepatotoxin; laboratory mouse; lipid peroxides; liver disorder; nitric oxide synthase; oxidative stress; toxin metabolism; transfection /expression vector

DESCRIPTION (provided by applicant): CYP2E1 activate many hepatotoxins and is induced under a variety of physiological and pathophysiological conditions, hence, studies on the biochemical and toxicological properties of CYP2E1 are important. Induction of CYP2E1 by ethanol is believed to be 1 of the central pathways by which ethanol generates a state of oxidative stress and causes hepatotoxicity. However, some studies recently have suggested that CYP2E1 may not play a role in alcohol liver injury based upon studies with gadolinium chloride or CYP2E1 knockout mice. Therefore, further studies are necessary to resolve the discrepancies over the role of CYP2E1 in alcohol-induced liver injury. In order to evaluate the biochemical and toxicological actions of CYP2E1 and its role in alcohol liver injury, an adenovirus which can mediate overexpression of CYP2E1 was constructed in our laboratory. This virus could express catalytic CYP2E1 in HepG2 cells, and it increased the sensitivity to acetaminophen induced toxicity in HepG2 cells. By injecting this virus into mice, we found that CYP2E1 protein and activity were elevated in the liver of the mice, and preliminary studies showed that it induced liver toxicity. The overall goal of this application is to focus on the use of this adenovirus mediated CYP2E1 expression model to evaluate the biochemical and toxicological properties of CYP2E1 and its role in the liver injury induced by alcohol administration. Studies will be carried out to evaluate molecular and cellular mechanisms responsible for the liver toxicity induced by ethanol which relates to CYP2E1. We hope this study could make a significant contribution to the prevention and therapy for alcohol liver disease, benefiting millions of such patients worldwide.

描述（由申请人提供）：CYP2E1激活许多肝毒素，并在多种生理和病理生理条件下诱导，因此，对CYP2E1生化和毒理学特性的研究很重要。据信乙醇诱导CYP2E1是乙醇产生氧化应激状态并引起肝毒性的中心途径的1。然而，一些研究最近表明，基于对氯化g或cyp2e1敲除小鼠的研究，CYP2E1可能在酒精肝损伤中发挥作用。因此，需要进一步的研究来解决CYP2E1在酒精诱导的肝损伤中的作用的差异。为了评估CYP2E1的生化和毒理学作用及其在酒精肝损伤中的作用，在我们的实验室中构建了一种可以介导CYP2E1过表达的腺病毒。该病毒可以在HEPG2细胞中表达催化CYP2E1，并提高对乙酰氨基酚诱导的HEPG2细胞毒性的敏感性。通过将这种病毒注射到小鼠中，我们发现CYP2E1蛋白和活性在小鼠的肝脏中升高，初步研究表明，它诱导了肝脏毒性。该应用的总体目的是专注于使用该腺病毒介导的CYP2E1表达模型来评估CYP2E1的生化和毒理学特性及其在酒精给药引起的肝损伤中的作用。将进行研究以评估负责与CYP2E1相关的乙醇引起的肝毒性的分子和细胞机制。我们希望这项研究可以为酒精肝病的预防和治疗做出重大贡献，从而使全球数百万此类患者受益。