THE ABILITY TO 4-HYDROXYLATE DEBRISOQUINE IS RELATED TO RECURRENCE OF BLADDER-CANCER

Oxidative metabolism by cytochrome P450 enzymes is often involved in the activation of environmental procarcinogens. Debrisoquine, mephenytoin, and dapsone were used as in vivo probes for the activities of P4502D6, 2C(MP), and 3A4, respectively, as well as dapsone for N-acetyltransferase, in order to assess the relationship between such activities and the relative risk of recurrence of bladder cancer. Urinary recovery ratios of debrisoquine and dapsone and the R/S ratio of mephenytoin were measured in an 0-8 h urine sample after simultaneous administration of debrisoquine (10 mg) and racemic mephenytoin (100 mg), and the administration of dapsone (100 mg) one week later, to patients undergoing local surgical resection of transitional cell bladder cancer of G-I, G-II, or G-III histopathology. In addition, plasma levels of dapsone and mono-acetyldapsone were determined in an 8 h plasma sample to determine the N-acetylation phenotype. Patients were followed for 3 years, to the time of tumour recurrence, or death. Three patients were lost to follow-up; of the remaining 9 5 patients, 55 had tumour recurrence. The debrisoquine recovery ratio was significantly greater in patients with recurrence than in individuals who remained disease-free. Among the 65 patients with non-aggressive (G-I and G-II) histopathology, two patients were lost to follow-up and 32 had tumour recurrence. In this subgroup, the debrisoquine recovery ratio was again found to be significantly greater in those individuals with tumour recurrence (p < 0.003). Analysis of Kaplan-Meier survival curves indicated that patients in the lowest tertile of debrisoquine hydroxylase activity were tumour-free for a longer time than those in the middle or upper tertiles of activity (p < 0.05) for both the whole group and the non-aggressive subgroup. Additionally, logistic regression analysis indicated a 6-7 fold relative risk for recurrence among patients with debrisoquine recovery ratios greater than 0.33 (p < 0.02). No differences in the mephenytoin R/S ratio, the dapsone recovery ratio, or N-acetylation phenotype were observed between patients who did or did not have a recurrence of their cancer, regardless of tumour histopathology. These observations are consistent with the hypothesis that debrisoquine 4-hydroxylase contributes to the activation of procarcinogens involved in tumour formation and recurrence, and suggest that assessment of P4502D6 activity may be useful as a prognostic indicator for bladder tumour recurrence following initial resection.