Aspects of human CYP 2E1 regulation in health and disease

Human cytochrome P4501 2E1 (CYP2E1) metabolizes a diverse group of xenobiotics, potentially resulting in chemical or immunologic hepatotoxicity or carcinogenesis. (CYP2E1) induction may be associated with increased risk of toxicity; inhibition may ameliorate the negative consequences of CYP2E1 metabolism. CYP2E1 activity increases in modestly obese subjects. However, the mechanism of this increase and in vivo regulation of human (CYP2E1) are poorly characterized. The purpose of these investigations is to identify: (1) the effect and mechanism of morbid obesity on (CYP2E1) activity and expression, (2) relationships between obesity-related hepatic disease and CYP2E1 activity, (3) the functional in vivo (CYP2E1) turnover in healthy subjects, and (4) the duration of inhibition following administration of the mechanism-based CYP2E1 inhibitor, disulfiram.; Compared to non-obese subjects, morbid obesity produced a fivefold increase in (CYP2E1) activity, measured as 6-hydroxylation of chlorzoxazone (CLZ), a selective in vivo CYP2E I probe. Plasma protein binding of CLZ increased by 60%. Accounting for the effect of these changes on hepatic CLZ clearance, there was a 2.7-fold induction of in vivo (CYP2E1) activity. A significant correlation between in vivo (CYP2E1) activity and body mass (r2 = 0.78) was observed. There is a greater degree of hepatic steatosis with teatosis with increased CYP2E1 activity. Post-gastroplasty weight loss in morbidly obese subjects accompanied the return of normal CYP2E1 activity. In contrast to in vivo results, no increase in hepatic microsomal immunoreactive CYP2E1 protein content was found in obese subjects. Hepatic microsomal CLZ Vmax and Km values were no different between obese and normal subjects, and there was poor predictability of in vivo CLZ hepatic intrinsic clearance from in vitro data. Cofactors and their activity (hepatic microsomial cytochrome b5, NADH or NADPH-dependent cytochrome c reduction, and significant NADH/NADPH effect in microsomal CLZ oxidation rates) failed to explain the obesity-related increase in vivo CYP2E1 activity. In healthy subjects, 95% inhibition of CYP2E1 activity was observed one day after a single dose of disulfiram. CYP2E1 activity returned to half that of control values by day 3, and to baseline values by day 8. The in vivo human CYP2E1 synthesis rate and degradation half-life were estimated at 11 +/- 5 nanomoles/hour and 50 +/- 19 hours, respectively.