CYP2A5 and alcoholic liver disease

CYP2A5 与酒精性肝病

基本信息

批准号：
8728699
负责人：
Yongke Lu
金额：
$ 23.63万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8728699
关键词：
7alpha hydroxylase Acute Alcohol consumption Alcoholic Liver Diseases Alcohols Animals Antioxidants Biological Assay Blood CYP1A2 gene CYP2A5 gene CYP2E1 gene CYP3A4 gene Categories Cause of Death Cell Culture Techniques Cell Death Chronic Clinical Coumarins Cytochrome P450 Data Diet Enzymes Ethanol Ethanol Metabolism Exploratory/Developmental Grant Feedback Genes Hepatic Human In Vitro Injury Link Liquid substance Liver Mediating Metabolism Microsomes Mixed Function Oxygenases Modeling Mus Nicotine Nuclear Oral Orthologous Gene Oxidation-Reduction Oxidative Stress Pathogenesis Patients Pharmaceutical Preparations Play Production Quality of life Rattus Reactive Oxygen Species Reporter Genes Reporting Response Elements Risk Factors Role Smooth Endoplasmic Reticulum System Therapeutic Intervention Toxic effect Transfection alpha benzopyrone chronic alcohol ingestion cytochrome P-450 CYP2A6 (human)design feeding global health improved in vitro Model in vivo liver injury microsomal ethanol-oxidizing system mouse model novel oxidation preconditioning promoter public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): Alcohol-induced liver injury is a significant global health problem and a leading cause of death worldwide. Understanding the mechanisms of this injury is critical for designing new therapies and improving the quality of life of many patients. The mechanisms by which ethanol treatment causes cell death are still not clear. Many of the hepatic toxic effects of ethanol have been linked to its metabolism in the liver. CYP2E1 can be induced by ethanol and is able to metabolize ethanol and is considered as one of the risk factors of alcoholic liver disease (ALD). It was reported that human hepatic CYP2A6 expression was increased in patients with ALD. In a mouse model, we found that mouse CYP2A5, the ortholog of CYP2A6, can be induced by chronic ethanol feeding to a much greater extent than CYP2E1, and very interestingly, ethanol induction of CYP2A5 in mice is CYP2E1-dependent. CYP2A5/6 metabolizes important clinical drugs such as coumarin, nicotine, nitroamines so its induction by ethanol is of major toxicological significance. In this Application, we move towards understanding whether mouse CYP2A5 may be involved in the pathogenesis of ALD. We hypothesize that CYP2E1-mediated ROS activates redox sensitive nuclear factor-eythroid 2-related factor 2 (Nrf2), and Nrf2 upregulates CYP2A5, which may metabolize ethanol and increase oxidative stress which contributes to pathogenesis of ALD i.e., CYP2E1 promotes ALD at least partially through CYP2A5. AIM 1 is designed to examine the possible role of ROS and Nrf2 in the induction of CYP2A5 by ethanol by using an in vivo ethanol feeding model and in vitro reporter gene transfection model. AIM 2 is designed to examine if CYP2A5 contributes to alcohol-induced liver injury. Cyp2a5-/- mice will be used to examine the possible role of CYP2A5 in pathogenesis of ALD, and cyp2a5 SiRNA will be applied to define the role of CYP2A5 in ethanol metabolism and ROS production and CYP2E1-mediated liver injury. Micosomes isolated from chronic ethanol liquid diet fed WT and cyp2a5-/- mice will be used to define hepatic microsomal ethanol metabolism and ROS production by CYP2A5. Ethanol induction of CYP2A5 and the role of CYP2E1 is a novel new finding, because most studies about microsomal ethanol metabolism were carried with rat microsomes, which lack CYP2A3, the ortholog of mouse CYP2A5. We think the experiments proposed in this Application fit in the category of the R21 mechanism, which supports exploratory studies. Hopefully, this study will answer the above questions and open a new window for ethanol metabolism and ALD study.

描述（由申请人提供）：酒精引起的肝损伤是全球重大的健康问题，也是全球死亡的主要原因。了解这种伤害的机制对于设计新疗法和改善许多患者的生活质量至关重要。乙醇治疗导致细胞死亡的机制仍不清楚。乙醇的许多肝毒性作用都与肝脏中的代谢有关。 CYP2E1可以由乙醇诱导，并能够代谢乙醇，并被认为是酒精性肝病（ALD）的危险因素之一。据报道，ALD患者的人肝CYP2A6表达增加。在小鼠模型中，我们发现小鼠CYP2A5（CYP2A6的直系同源物）可以通过慢性乙醇进食的程度要比CYP2E1诱导，并且非常有趣的是，小鼠中CYP2A5的乙醇诱导是CYP2E1依赖性的。 CYP2A5/6代谢重要的临床药物，例如香豆素，尼古丁，硝胺，因此乙醇的诱导具有主要的毒理学意义。在此应用中，我们朝着了解小鼠CYP2A5是否可能参与ALD的发病机理。 We hypothesize that CYP2E1-mediated ROS activates redox sensitive nuclear factor-eythroid 2-related factor 2 (Nrf2), and Nrf2 upregulates CYP2A5, which may metabolize ethanol and increase oxidative stress which contributes to pathogenesis of ALD i.e., CYP2E1 promotes ALD at least partially through CYP2A5. AIM 1旨在通过使用体内乙醇进食模型和体外报告基因转染模型来检查乙醇通过乙醇诱导CYP2A5在诱导CYP2A5中的可能作用。 AIM 2旨在检查CYP2A5是否有助于酒精诱导的肝损伤。 CYP2A5 - / - 小鼠将用于检查CYP2A5在ALD发病机理中的可能作用，并且CYP2A5 siRNA将用于定义CYP2A5在乙醇代谢中的作用，ROS产生和CYP2E1介导的肝损伤。从慢性乙醇液体饮食中分离出的MICOSOMES将使用CYP2A5定义肝微粒体乙醇代谢和ROS产生。 CYP2A5的乙醇诱导和CYP2E1的作用是一个新颖的新发现，因为大多数关于微粒体乙醇代谢的研究都是用大鼠微粒体进行的，后者缺乏小鼠CYP2A5的cyp2a3。我们认为，此应用中提出的实验符合R21机制的类别，该机制支持探索性研究。希望这项研究能够回答上述问题，并为乙醇代谢和ALD研究打开新窗口。