Human CYP2B6 in alcohol metabolism and alcoholic liver injury

项目摘要： 过度饮酒是造成全球发病率和死亡率负担的主要因素， 酒精性肝病（ALD）的原因，占全球酒精相关死亡的25%。 ALD的范围从相对轻度的肝脂肪变性、酒精性脂肪性肝炎和纤维化， 不可逆肝硬化和肝细胞癌。流行病学研究表明，酗酒，高- 风险酒精消费方式，已成为越来越受欢迎的年轻人;和频繁的狂欢 饮酒者患严重酒精性肝病的风险更高。然而，酗酒的潜在机制- 诱导的肝损伤和是否有一个适应性的酶系统，代谢高浓度的 酗酒后的酒精是知之甚少。我们的初步数据表明，慢性乙醇 喂食加暴饮暴食显著诱导细胞色素P450 2b 10的肝脏表达 （Cyp2b10）。在酒精狂饮后，Cyp 2b 10基因敲除小鼠的血液乙醇水平显著升高， 高于野生型小鼠。此外，长期加酗酒酒精喂养导致更大的肝脏 Cyp 2b 10基因敲除小鼠中的损伤比野生型小鼠中的损伤小。这些令人兴奋的发现导致了 假设人CYP 2B 6，鼠CYP 2B 10的类似物，在狂饮中起重要作用- 诱导ALD，而CYP 2B 6酶的适应性诱导协调了一种新的保护机制 潜在的ALD。我们将在两个提出的具体目标中检验这一假设：目标1是确定CYP 2B 6- 目的2将研究CYP 2B 6在乙醇中的作用 在人源化小鼠模型中的暴食诱导的肝损伤。这些研究将为以下方面提供必要的基础： 确定并验证CYP 2B 6/Cyp 2b 10介导的适应性代谢的新代谢途径 以及在暴饮暴食后对过量酒精的解毒。

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.