Premium
Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis
Author(s) -
Chalasani Naga,
Gorski J. Christopher,
Asghar Maleeha S.,
Asghar Ali,
Foresman Brian,
Hall Stephen D.,
Crabb David W.
Publication year - 2003
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2003.50095
Subject(s) - medicine , endocrinology , cyp2e1 , insulin resistance , pathogenesis , hypoxemia , insulin , chemistry , cytochrome p450 , metabolism
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 β‐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 × 10 3 ± 10 × 10 3 vs. 2.6 × 10 3 ± 1.2 × 10 3 molecules/μg total RNA, respectively, P < .001). On univariate analysis, BMI, respiratory quotient, high‐density lipoprotein, triglycerides, insulin, insulin resistance, hypoxemia, and β‐OH butyrate significantly correlated with hepatic CYP2E1 activity. However, on stepwise regression analysis, only nocturnal hypoxemia ( r = 0.50, P = .009) and β‐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 β‐OH butyrate suggest that these factors play a role in increased CYP2E1 activity that is seen in patients with NASH.