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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要：过量饮酒是全球发病率和死亡率负担的一个主要原因，并且酒精性肝病 (ALD) 的病因占全球酒精相关死亡人数的 25%。 ALD 的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，酗酒是一种高风险饮酒方式，已越来越受到年轻人的青睐；以及频繁的暴饮暴食饮酒者患严重酒精性肝病的风险较高。然而，酗酒背后的机制是诱导的肝损伤以及是否存在代谢高浓度的适应性酶系统人们对酗酒后的乙醇知之甚少。我们的初步数据表明，长期乙醇喂食加暴饮暴食会显着诱导细胞色素 P450 2b10 的肝脏表达 (Cyp2b10) 在小鼠中。酗酒后，Cyp2b10缺失小鼠的血液乙醇水平显着升高高于野生型小鼠。此外，长期加暴食乙醇会导致肝脏损伤更大。 Cyp2b10 缺失小鼠的损伤程度高于野生型小鼠。这些令人兴奋的发现导致了总体假设人类 CYP2B6（鼠 Cyp2b10 的类似物）在酗酒中发挥重要作用 - 诱导 ALD，并且 CYP2B6 酶的适应性诱导协调一种新的保护机制潜在的 ALD。我们将在两个提出的具体目标中测试这一假设：目标 1 是确定 CYP2B6- 介导人肝细胞中乙醇的代谢；目标 2 将研究 CYP2B6 在乙醇中的作用人源化小鼠模型中暴食引起的肝损伤。这些研究将为以下方面提供必要的基础：识别并验证由 CYP2B6/Cyp2b10 介导的适应性代谢的新代谢途径以及暴饮后过量酒精的解毒。