The hypothesis that the frequency distribution of indices of oxidative
drug-metabolizing activity is different between patients with
bladder cancer (n = 98) and age, sex-matched control subjects (n = 110) has been investigated. Urinary recovery ratios of
debrisoquine and R/S ratios of
mephenytoin have been measured in an 8-h urine sample after simultaneous administration of
debrisoquine (10 mg) and racemic
mephenytoin (100 mg). In addition, alcohol consumption, smoking habit, and acetylation phenotype (using 100 mg
dapsone as a substrate) have been measured. Patients with
bladder cancer were classified on histological criteria as having aggressive (Stage III) (34%) or nonaggressive (Stages I and II) (66%) disease. The median of the frequency distribution of the
debrisoquine urinary recovery ratio in patients with aggressive
bladder cancer was greater than in control subjects, and only four patients had recovery ratios lower than the mean of the control group. Using logistic regression analysis, efficient
debrisoquine metabolism and a synergistic interaction between smoking and
ethanol consumption were significant, independent risk factors, while S-
mephenytoin hydroxylation and acetylation phenotype were not significant risk factors. In contrast, patients with non-aggressive
bladder cancer had a significant, but weaker, association with rapid hydroxylation of S-
mephenytoin, which was independent of a significant synergistic interaction between smoking and alcohol consumption. Acetylation phenotype and
debrisoquine urinary recovery ratio were not associated with increased risk of nonaggressive
cancer. These results are consistent with the concept that oxidative
isozymes might be responsible for conversion of environmental agents to proximate bladder
carcinogens in nonindustrial-related
bladder cancer. They also suggest that different etiological factors are involved in the pathogenesis of aggressive and nonaggressive
bladder cancer.