title: Low activity of dapsone N-hydroxylation as a susceptibility risk factor in aggressive bladder cancer.
abstract: N-arylamines involved in the pathogenesis of bladder cancer, require metabolic activation via N-hydroxylation. The efficiency of in vivo N-hydroxylation of dapsone, a non-carcinogenic arylamine, may, therefore, provide a host susceptibility measure of risk of developing bladder cancer. To investigate this possibility, the dapsone recovery ratio, a phenotypic measure of the efficiency of dapsone hydroxylation, has been measured in a case control study in an urban UK population, comparing patients with aggressive bladder cancer (n = 33), non-aggressive bladder cancer (n = 60) and controls (n = 108). Dapsone recovery ratio in controls exhibited a unimodal distribution. Patients with aggressive bladder cancer had a similar distribution but significantly lower mean value (p < 0.005). Logistic regression analysis, controlling for sex, age, smoking habit and alcohol consumption confirmed a significant (p < 0.05) association between the dapsone recovery ratio and aggressive bladder cancer. Subjects in the lowest tertile of dapsone recovery ratio had a relative risk to 5.4-fold greater than subjects in the upper tertile (p < 0.009), and a trends test was significant (p < 0.001). There was no significant association between dapsone recovery ratio and non-aggressive bladder cancer. These results do not support the hypothesis that the drug metabolizing enzymes involved in dapsone N-hydroxylation are involved in causing bladder cancer. Instead, they suggest the opposite, the observation that low enzyme activity was associated with increased risk is consistent with this enzyme providing a detoxification mechanism for environmental procarcinogens.
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: C M
authors.initials: CM
authors.lastname: Fleming
authors.forename: R
authors.initials: R
authors.lastname: Persad
authors.forename: A
authors.initials: A
authors.lastname: Kaisary
authors.forename: P
authors.initials: P
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Adedoyin
authors.forename: J
authors.initials: J
authors.lastname: Porter
authors.forename: G R
authors.initials: GR
authors.lastname: Wilkinson
authors.forename: R A
authors.initials: RA
authors.lastname: Branch
mesh_terms: D016022:Case-Control Studies; D003622:Dapsone / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D006900:Hydroxylation; D008658:Inactivation, Metabolic; D010641:Phenotype; D012307:Risk Factors; D006113:United Kingdom / Q000453:epidemiology; D001749:Urinary Bladder Neoplasms / Q000453:epidemiology* / Q000378:metabolism / Q000473:pathology
chemical_list: D003622:Dapsone