Published in Cancer Detection and Prevention 1993; 17(1).

Debrisoquine and dapsone hydroxylation as risk factors in human bladder carcinogenesis

Branch, R., Persad, R., Fleming, C., Adedoyin, A., Sibley, G., Smith, P., Wilkinson, G.R.

Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Division of Clinical Pharmacology, Vanderbilt University, and Department of Urology, Bristol University, U.K.

Bladder carcinogenesis in man can be induced by conversion of environmental procarcinogens to proximate carcinogens by drug metabolizing enzymes. However, the specific individual enzymes and procarcinogens involved in non-industrial urban bladder cancer in man have not been identified. Measures of the efficiency of debrisoquine (DB) and dapsone (DDS) hydroxylation -have been shown to be specific in vivo probes of activity of cytochrome P4502D6 and P4053A4, respectively. These provide measures to evaluate the activity of these specific isozymes to the risk of developing bladder cancer. Phenotypic traits of their activity were evaluated in 64 patients with aggressive bladder cancer (GIII or IV histopathology) and 85 controls following simultaneous single dose administration in an urban U.K. population. The cancer group had a significantly lower incidence of poor metabolizers of DB (1.7% versus 9%). The unimodal distribution of DDS hydroxylation was significantly lower in the cancer group than in the control group. Logistic regresssion confirmed that subjectswho were both extensive metabolizers of DB and had a phenotypic trait for DDS that was below the mean of normals were at high risk. These results identify risk factors for developing bladder cancer and are consistent with the environmental procarcinogen hypothesis in human bladder cancer.

Paper presented at the International Symposium on Genetic Factors in Predictive and Preventive Oncology; Nice, France; March 14-16, 1993; in the section on Prognostic Indicators.