Environmental procarcinogen hypothesis of bladder cancer in humans: Dapsone hydroxylation as a susceptibility risk factor for aggressive bladder cancer

Abstract

The dapsone recovery ratio (DPRR), which is determined after single oral dose administration of dapsone by measuring the parent drug and hydroxylated metabolite, provides an in vivo measure of the efficiency of the drug metabolizing enzymes responsible for this metabolic route, putatively CYP3A4. This affords the potential to evaluate the hypothesis that this drug metabolizing enzyme system is involved in the pathogenesis of human bladder cancer. The present study is a matched case-control comparison of DPRR in patients with nonaggressive bladder cancer (grades I and II or Ta, T1 and T2, n = 43), patients with aggressive bladder cancer without invasion (grade III or Ta, T1 and T2, n = 32), patients with aggressive bladder cancer and invasion (grade III or T3 and T4, n = 32), and age- and gender-matched subjects with no urologic tumor on cystoscopy from an urban U.K. community (n = 85). Demographic variables associated with aggressive bladder cancer (Gill or T3, T4, Tis) included pack-years of smoking, alcohol intake, and occupational exposure; for nonaggressive bladder cancer variables included smoking and occupational exposure. DPRR exhibited an unimodal distribution in all subjects: activity was significantly reduced in both noninvasive and invasive aggressive bladder cancer, and was a significant risk factor for cancer after adjustment for other significant risk factors. Combining the two aggressive groups, the lowest tertile of DPRR activity was associated with a sixfold increase in risk ( p < 0.02) compared with the upper tertile. We conclude that a low dapsone recovery ratio is an independent risk factor for aggressive bladder cancer irrespective of its stage of invasion and suggest that the enzymes involved in its metabolism are detoxifying enzymes for unknown environmental factors to which an urban community is exposed.