CORRELATION OF POLYMORPHIC EXPRESSION OF CYP2D6 MESSENGER-RNA IN BLADDER MUCOSA AND TUMOR-TISSUE TO IN-VIVO DEBRISOQUINE HYDROXYLASE-ACTIVITY

Debrisoquine hydroxylase activity has been attributed to CYP2D6 and po or metabolizers of debrisoquine have a reduced relative risk of develo ping aggressive bladder cancer. Production of a proximate carcinogen c ould occur in liver or bladder mucosa. However, it is not known if CYP 2D6 is expressed in human bladder mucosa, In vivo whole body debrisoqu ine hydroxylase activity was measured as the debrisoquine recovery rat io (DBRR) following single dose oral administration of debrisoquine (1 0 mg) in 10 normal subjects and 20 patients with bladder cancer prior to diagnostic cystoscopy. Semi-quantitative PCR was used to measure mR NA for CYP2D6 in bladder tissue obtained at cystoscopy, Of the 30 subj ects, three were phenotypically and genotypically poor metabolizers. A mong the extensive metabolizers, there were extensive intersubject var iations in DBRR. A 10-fold variation in CYP2D6 mRNA levels was observe d in bladder tissue. There was a highly significant association betwee n DBRR and CYP2D6 mRNA expression (r(2) = 0.702, P < 0.001). These res ults demonstrate the presence of CYP2D6 mRNA in bladder mucosa. Furthe rmore, they are consistent with debrisoquine hydroxylation being media ted by CYP2D6 and suggest that differences in mRNA concentration are r ate limiting for enzyme activity and that bladder mucosal regulation r eflects total body regulation for this enzyme, The expression of CYP2D 6 in bladder mucosa suggests that this enzyme could be involved in the local production of a proximate carcinogen in this tissue and contrib ute to the pathogenesis of bladder cancer in man.