Changes in microsomal activity in alcoholism and obesity

Background: Liver damage is more prevalent among obese alcoholics, and cyto chrome P-450-2E1(CYP2E1) induction is involved in its pathogenesis. Objectives: The study was undertaken to assess microsomal function, in alco holic and nonalcoholic male subjects with different body compositions, thro ugh pharmacokinetics of chlorzoxazone (CLZ). We also intended to study the relationship between CLZ hydroxylation and urinary levels of 8-hydroxydigua nosine, and between CLZ levels and liver histology. Methods: Serial measurements of CLZ serum concentration, after a 750 mg dos e, were performed in 17 alcoholics (9 normal weight and 8 obese) and 21 non alcoholic subjects (10 normal weight and 11 obese). Concentration of 6-hydr oxy-chlorzoxazone (6-OH-CLZ) was determined at the second hour. Anthropomet ry, clinical laboratory tests, and urinary 8-hydroxydiguanosine concentrati ons were measured. Liver biopsies were performed in alcoholics. Results: Five biopsies revealed severe lesions, one in normal-weight and fo ur in obese patients (p = NS). Area under the curve (AUC) of CLZ was higher in normal-weight controls compared with the rest of the groups (ANOVAp = 0 .001). This parameter correlated negatively with adiposity in nonalcoholic subjects and did not correlate with liver histology. 6-OH-CLZ/CLZ ratio was lower in normal-weight controls, compared with obese subjects and normal-w eight alcoholics (p = 0.02). Both alcoholism and obesity were included as p redictors of CLZ AUC in a multiple regression analysis. The two-factor ANOV A showed an additive effect of centripetal body fat distribution and alcoho lism. Urinary 8-hydroxydiguanosine levels were extremely variable. Conclusions: Centripetal adiposity and alcoholism are associated with induc tion of CYP2E1. This may explain the higher prevalence of liver damage amon g obese alcoholics and also nonalcoholic steatohepatitis.