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.

Narrative The proposed studies will yield novel knowledge regarding the role of human CYP2B6 in alcohol metabolism and alcoholic liver disease. The anticipated outcomes will offer proof-of-concept evidence that CYP2B6 metabolizes high concentrations of ethanol after binge drinking, and adaptive upregulation of CYP2B6 ameliorates acute-on-chronic ethanol-induced liver injury.