Human CYP2B6 in alcohol metabolism and alcoholic liver injury

项目总结： 过度饮酒是造成全球发病率和死亡率负担的主要因素，而且 酒精性肝病(ALD)的原因，占全球与酒精相关的死亡人数的25%。 ALD的范围从相对轻微的肝脏脂肪变性、酒精性脂肪性肝炎和纤维化，到 不可逆性肝硬变和肝细胞癌。流行病学研究表明，酗酒是一种高... 冒险的饮酒方式，在年轻人中越来越受欢迎；经常酗酒 饮酒者患严重ALD的风险更高。然而，酒精狂欢背后的机制- 诱导的肝损伤，以及是否有一个适应的酶系统来代谢高浓度的 人们对酗酒后的乙醇知之甚少。我们的初步数据表明，慢性乙醇 喂食和暴食显著诱导肝脏细胞色素P450 2b10的表达 (Cyp2b10)。在酗酒后，Cyp2b10基因缺失小鼠的血液酒精水平显著 高于野生型小鼠。此外，长期过量饮酒会导致肝脏变大。 Cyp2b10基因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 假设人的CYP2B6，类似于小鼠的Cyp2b10，在酗酒中起着重要作用- 诱导ALD，而CYP2B6酶适应性诱导协调了一种新的保护机制 潜在的阿尔茨海默病。我们将在两个提出的具体目标中检验这一假设：目标1是确定CYP2B6- 介导乙醇在人肝细胞中的代谢；Aim 2将研究CYP2B6在乙醇中的作用 暴饮暴食致人源化小鼠肝损伤模型。这些研究将为以下工作提供必要的基础 发现和验证一条新的代谢途径--由CYP2B6/Cyp2b10介导的适应性代谢 暴饮暴食后过量饮酒的解毒。

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.