Changes in Microsomal Activity in Alcoholism and Obesity

Abstract

Background: Liver damage is more prevalent among obese alcoholics, and cytochrome P-450 -2E1(CYP2E1) induction is involved in its pathogenesis.Objectives: The study was undertaken to assess microsomal function, in alcoholic and nonalcoholic male subjects with different body compositions, through pharmacokinetics of chlorzoxazone (CLZ). We also intended to study the relationship between CLZ hydroxylation and urinary levels of 8-hydroxydiguanosine, and between CLZ levels and liver histology.Methods: Serial measurements of CLZ serum concentration, after a 750 mg dose, were performed in 17 alcoholics (9 normal weight and 8 obese) and 21 nonalcoholic subjects (10 normal weight and 11 obese). Concentration of 6-hydroxy-chlorzoxazone (6-OH-CLZ) was determined at the second hour. Anthropometry, clinical laboratory tests, and urinary 8-hydroxydiguanosine concentrations were measured. Liver biopsies were performed in alcoholics.Results: Five biopsies revealed severe lesions, one in normal-weight and four in obese patients (p ϭ NS). Area under the curve (AUC) of CLZ was higher in normal-weight controls compared with the rest of the groups (ANOVA p ϭ 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-weight alcoholics (p ϭ 0.02). Both alcoholism and obesity were included as predictors of CLZ AUC in a multiple regression analysis. The two-factor ANOVA showed an additive effect of centripetal body fat distribution and alcoholism. Urinary 8-hydroxydiguanosine levels were extremely variable.Conclusions: Centripetal adiposity and alcoholism are associated with induction of CYP2E1. This may explain the higher prevalence of liver damage among obese alcoholics and also nonalcoholic steatohepatitis.

Impaired 6-hydroxychlorzoxazone elimination in patients with kidney disease: implication for cytochrome P450 2E1 pharmacogenetic studies

“…Our finding of a positive relationship between body weight and CYP2E1 activity is in agreement with previous studies 3 , 19 , 55 , 56 , 57 . O'Shea et al 3 reported that HCZ formation clearance was more than 50% higher in obese subjects with normal renal function than in control subjects.…”

“…In conclusion, this study shows that impaired HCZ elimination leads to accumulation of the metabolite in plasma, which causes an elevation in the CZ MR values independent of any effect on CYP2E1 activity, thereby effectively invalidating the MR as a phenotypic trait measure. In addition, this study confirms previous findings of a significant relationship between weight and CYP2E1 activity 3 , 19 , 55 , 56 , 57 and demonstrates that obesity together with kidney disease results in dramatically increased CZ MR values. This finding hasimportant implications to those involved in clinical pharmacogenetic studies using CZ as a phenotypic probe, becauseit may lead to incorrect phenotypic classifications and inaccurate conclusions surrounding the corresponding susceptibility to chemical toxicity and cancer.…”

“…These findings could have important clinical consequences, because overweight individuals with enhanced CYP2E1 activity would be expected to be at increased risk from the adverse effects of CYP2E1‐mediated bioactivation of toxins and carcinogens. Indeed, obesity is a risk factor for alcohol‐induced hepatotoxicity, 58 and recent studies have used CZ as a phenotypic probe in obese alcoholic subjects to estimate their susceptibility to hepatotoxicity 19 . Failure to appreciate the impact of renal function on the phenotypic trait measure in these types of subjects could confound the results, because increased weight in individuals with reduced renal function appears to have at least additive effects on the CZ MR (Fig 7).…”

“…Although it is currently of limited use therapeutically, CZ is used extensively as a phenotypic probe because of its relative safety and selectivity for CYP2E1 10 . It has been used in several studies assessing the impact of various conditions 2 , 3 , 10 , 13 , 18 , 19 and pharmacotherapy 20 , 21 , 22 , 23 on CYP2E1 activity. CZ currently remains the only validated pharmacologic probe for CYP2E1 in humans.…”