Chalasani Naga, Gorski J Christopher, Asghar Maleeha S, Asghar Ali, Foresman Brian, Hall Stephen D, Crabb David W
Division of Gastroenterology/Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Hepatology. 2003 Mar;37(3):544-50. doi: 10.1053/jhep.2003.50095.
Cytochrome P450 2E1 (CYP2E1) plays an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH) in animal models, but its role in the pathogenesis of human NASH is unclear. Therefore, we measured hepatic CYP2E1 activity and its correlates in a cohort of nondiabetic patients with NASH (NDN) and controls to explore its role in the pathogenesis of human NASH. Hepatic CYP2E1 activity was assessed using the oral clearance (CL(PO)) of chlorzoxazone (CHZ) in 20 NDN and 17 age, gender, and body mass index (BMI)-matched controls. The relationship between hepatic CYP2E1 activity and demographic and anthropometric variables; fasting levels of insulin, glucose, lipids, and beta-OH butyrate; insulin resistance; and nocturnal hypoxemia was assessed. Furthermore, expression of CYP2E1 in the peripheral lymphocytes was assessed using reverse transcription-polymerase chain reaction (RT-PCR). The CL(PO) of CHZ was significantly (P =.03) greater in NDN (41 +/- 12 L/h) compared with controls (33 +/- 16 L/h). Lymphocyte CYP2E1 messenger RNA was significantly higher in NDN compared with controls (11.5 x 10(3) +/- 10 x 10(3) vs. 2.6 x 10(3) +/- 1.2 x 10(3) molecules/microg total RNA, respectively, P <.001). On univariate analysis, BMI, respiratory quotient, high-density lipoprotein, triglycerides, insulin, insulin resistance, hypoxemia, and beta-OH butyrate significantly correlated with hepatic CYP2E1 activity. However, on stepwise regression analysis, only nocturnal hypoxemia (r = 0.50, P =.009) and beta-OH butyrate (r = 0.37, P =.04) were independent predictors of hepatic CYP2E1 activity. In conclusion, hepatic CYP2E1 activity and lymphocyte CYP2E1 expression are enhanced in NDN. The significant correlations noted between CYP2E1 and hypoxemia and beta-OH butyrate suggest that these factors play a role in increased CYP2E1 activity that is seen in patients with NASH.
细胞色素P450 2E1（CYP2E1）在动物模型的非酒精性脂肪性肝炎（NASH）发病机制中起重要作用，但其在人类NASH发病机制中的作用尚不清楚。因此，我们在一组非糖尿病NASH患者（NDN）和对照组中测量了肝脏CYP2E1活性及其相关指标，以探讨其在人类NASH发病机制中的作用。使用氯唑沙宗（CHZ）的口服清除率（CL(PO)）评估了20例NDN患者和17例年龄、性别及体重指数（BMI）匹配的对照者的肝脏CYP2E1活性。评估了肝脏CYP2E1活性与人口统计学和人体测量学变量、空腹胰岛素、葡萄糖、脂质和β-羟基丁酸水平、胰岛素抵抗及夜间低氧血症之间的关系。此外，使用逆转录-聚合酶链反应（RT-PCR）评估了外周淋巴细胞中CYP2E1的表达。与对照组（33±16 L/h）相比，NDN患者的CHZ的CL(PO)显著更高（P = 0.03）（41±12 L/h）。与对照组相比，NDN患者淋巴细胞CYP2E1信使核糖核酸显著更高（分别为11.5×10³±10×10³与2.6×10³±1.2×10³分子/μg总RNA，P < 0.001）。单因素分析显示，BMI、呼吸商、高密度脂蛋白、甘油三酯、胰岛素、胰岛素抵抗、低氧血症和β-羟基丁酸与肝脏CYP2E1活性显著相关。然而，逐步回归分析显示，仅夜间低氧血症（r = 0.50，P = 0.009）和β-羟基丁酸（r = 0.37，P = 0.04）是肝脏CYP2E1活性的独立预测因素。总之，NDN患者肝脏CYP2E1活性和淋巴细胞CYP2E1表达增强。CYP2E1与低氧血症和β-羟基丁酸之间的显著相关性表明，这些因素在NASH患者中观察到的CYP2E1活性增加中起作用。
