Changes in microsomal activity in alcoholism and obesity.
BACKGROUND
Liver damage is more prevalent among obese alcoholics, and cytochrome P-4502E1(CYP2E1) induction is involved in its pathogenesis.


OBJECTIVE
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 = NS). Area under the curve (AUC) of CLZ was higher in normal-weight controls compared with the rest of the groups (ANOVA p = 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 = 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.
de la Maza
M P
MP
San Borja-Arriarán Hospital and Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago. mpmaza@uec.inta.uchile.cl
Hirsch
S
S
Petermann
M
M
Suazo
M
M
Ugarte
G
G
Bunout
D
D
D000328:Adult; D000437:Alcoholism / Q000201:enzymology*; D000704:Analysis of Variance; D002753:Chlorzoxazone / Q000097:blood / Q000493:pharmacokinetics*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D009125:Muscle Relaxants, Central / Q000097:blood / Q000493:pharmacokinetics*; D009765:Obesity / Q000201:enzymology*
D009125:Muscle Relaxants, Central; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone