Human CYP2B6 in alcohol metabolism and alcoholic liver injury

人CYP2B6在酒精代谢和酒精性肝损伤中的作用

• 批准号: 10037957
• 负责人: Hongbing Wang
• 金额: $ 22.21万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10037957
• 关键词: Acetaldehyde; Acute; Affect; Agonist; Alcohol consumption; Alcohol dehydrogenase; Alcoholic Liver Diseases; Alcoholic steatohepatitis; Alcohols; Arizona; Biological Assay; Blood; CYP1A2 gene; CYP2B6 gene; CYP2E1 gene; CYP3A4 gene; Cause of Death; Cell Culture Techniques; Cessation of life; Chronic; Cirrhosis; Clinical; Cytochrome P450; Data; Drug Metabolic Detoxication; Drug usage; Enzymes; Ethanol; Ethanol Metabolism; Excretory function; Experimental Models; Fatty Liver; Fibrosis; Future; Genes; Heavy Drinking; HepG2; Hepatic; Hepatocyte; Human; In Vitro; Ingestion; Injections; Intake; Investigation; Kinetics; Knockout Mice; Knowledge; Letters; Liver; Liver diseases; Mediating; Metabolic; Metabolic Pathway; Metabolism; Microsomes; Mitochondria; Monoclonal Antibodies; Morbidity - disease rate; Mus; Outcome; Oximes; Pathologic; Patients; Pharmaceutical Preparations; Play; Prevalence; Primary carcinoma of the liver cells; Prodrugs; Propane; Research; Role; System; Tail; Testing; Thiazoles; Transcriptional Regulation; United States; Universities; Up-Regulation; Veins; Wild Type Mouse; Xenobiotics; acetaldehyde dehydrogenase; alcohol misuse; alcohol use disorder; analog; base; binge drinker; binge drinking; chronic alcohol ingestion; chronic liver disease; constitutive androstane receptor; cytotoxicity; defined contribution; epidemiology study; feeding; high risk; humanized mouse; improved; in vivo; inhibitor/antagonist; liver injury; loss of function; mortality; mouse model; novel; overexpression; oxidation; receptor expression; response; stable cell line; transcription factor; young adult

Project Summary: Excessive consumption of alcohol is a major contributor to the global burden of morbidity and mortality, and is the cause of alcoholic liver disease (ALD) that accounts for up to 25% of alcohol-associated deaths worldwide. The spectrum of ALD ranges from relatively mild hepatic steatosis, alcoholic steatohepatitis and fibrosis, to irreversible cirrhosis and hepatocellular carcinoma. Epidemiological studies reveal that binge drinking, a high- risk alcohol consumption style, has become increasingly popular among young adults; and frequent binge drinkers are at higher risk for developing severe ALD. However, the mechanisms underlying alcohol binge- induced liver injury and whether there is an adaptive enzymatic system that metabolizes high concentrations of ethanol after binge drinking are poorly understood. Our preliminary data demonstrate that chronic ethanol feeding plus binge administration drastically induces hepatic expression of the cytochrome P450 2b10 (Cyp2b10) in mice. After alcohol binge ingestion blood ethanol levels of Cyp2b10-null mice were significantly higher than that of wild-type mice. Moreover, chronic-plus-binge ethanol feeding resulted in greater liver damage in Cyp2b10-null mice than that in wild-type mice. These exciting findings have led to the overarching hypothesis that human CYP2B6, the analog of murine Cyp2b10, plays an important role in binge drinking- induced ALD, and that adaptive induction of CYP2B6 enzyme coordinates a novel protective mechanism underlying ALD. We will test this hypothesis in two proposed specific aims: Aim 1 is to determine CYP2B6- mediated metabolism of ethanol in human liver cells; and Aim 2 will investigate the role of CYP2B6 in ethanol binge-induced liver injury in humanized mouse model. These studies will provide necessary groundwork for identifying and validating a novel metabolic pathway-mediated by CYP2B6/Cyp2b10 for adaptive metabolism and detoxification of excessive alcohol after binge ingestion.

项目摘要： 过度食用酒精是全球发病和死亡负担的主要原因，并且是 酒精性肝病（ALD）的原因最多占全球酒精相关死亡的25％。 ALD的光谱范围从相对轻微的肝脂肪变性，酒精性脂肪性肝炎和纤维化，到 不可逆的肝硬化和肝细胞癌。流行病学研究表明，暴饮暴食，高度 风险饮酒风格，在年轻人中变得越来越受欢迎。和频繁的狂欢 饮酒者患严重ALD的风险更高。但是，酒精暴饮暴食的基础机制 诱发肝损伤以及是否有一种自适应酶系统代谢高浓度 暴饮暴食后的乙醇知之甚少。我们的初步数据表明慢性乙醇 进食加狂饮急剧诱导细胞色素P450 2B10的肝表达 （CYP2B10）在小鼠中。酒精暴饮暴食后，CYP2B10-NULL小鼠的血液乙醇水平显着 高于野生型小鼠。此外，慢性加仑乙醇喂养导致更大的肝脏 CYP2B10-NULL小鼠的损害比野生型小鼠的损伤。这些令人兴奋的发现导致了总体 假设人CYP2B6（鼠CYP2B10的类似物）在暴饮暴食中起着重要作用 诱导的ALD，并且CYP2B6酶的自适应诱导辅助了一种新型的保护机制 基础ALD。我们将以两个提出的特定目的来检验这一假设：目标1是确定CYP2B6-- 人肝细胞中乙醇的介导的代谢； AIM 2将研究CYP2B6在乙醇中的作用 人性化小鼠模型中暴饮暴食诱导的肝损伤。这些研究将为 识别和验证由CYP2B6/CYP2B10介导的新型代谢途径用于自适应代谢 饮食后过量酒精的排毒。