Correlation of polymorphic expression of CYP2D6 mRNA in bladder mucosa and tumor tissue to in vivo debrisoquine hydroxylase activity

Abstract

Debrisoquine hydroxylase activity has been attributed to CYP2D6 and poor metabolizers of debrisoquine have a reduced relative risk of developing aggressive bladder cancer. Production of a proximate carcinogen could occur in liver or bladder mucosa. However, it is not known if CYP2D6 is expressed in human bladder mucosa. In vivo whole body debrisoquine hydroxylase activity was measured as the debrisoquine recovery ratio (DBRR) following single dose oral administration of debrisoquine (10 mg) in 10 normal subjects and 20 patients with bladder cancer prior to diagnostic cystoscopy. Semi-quantitative PCR was used to measure mRNA for CYP2D6 in bladder tissue obtained at cystoscopy. Of the 30 subjects, three were phenotypically and genotypically poor metabolizers. Among the extensive metabolizers, there were extensive intersubject variations in DBRR. A 10-fold variation in CYP2D6 mRNA levels was observed in bladder tissue. There was a highly significant association between DBRR and CYP2D6 mRNA expression (r2 = 0.702, P < 0.001). These results demonstrate the presence of CYP2D6 mRNA in bladder mucosa. Furthermore, they are consistent with debrisoquine hydroxylation being mediated by CYP2D6 and suggest that differences in mRNA concentration are rate limiting for enzyme activity and that bladder mucosal regulation reflects total body regulation for this enzyme. The expression of CYP2D6 in bladder mucosa suggests that this enzyme could be involved in the local production of a proximate carcinogen in this tissue and contribute to the pathogenesis of bladder cancer in man.

Association of DNA Repair and Steroid Metabolism Gene Polymorphisms with Clinical Late Toxicity in Patients Treated with Conformal Radiotherapy for Prostate Cancer

“…Tissue-specific expression of CYP2D6 in extrahepatic tissues, such as bladder, as well as an association of CYP2D6 alleles in prostate cancer, has been reported (51,52). Despite the marginal association in multivariate analysis between CYP2D6*4 and radiation toxicity described in this article, a putative role of CYP2D6 in tissue damage or repair has not been clearly established.…”

Coordinated intrahepatic and extrahepatic regulation of cytochrome P4502D6 in healthy subjects and in patients after liver transplantation

“…With this technique, the concentrations of mRNA for CYP2D6 have been compared in a variety of tissues, including the bladder, 17 lung, 18 oral mucosa 38 , and PBMCs, 19 , 20 and were compared with liver concentrations. In this study, concentrations of mRNA for CYP2D6 were approximately 2‐fold greater in the liver than in PBMCs.…”

“…We have previously reported a small study of 12 EMs of CYP2D6 with mixed cancer diagnoses in whom concentrations of mRNA for CYP2D6 in PBMCs were associated with in vivo CYP2D6 enzyme activity, as measured by the metabolism of debrisoquin to hydroxydebrisoquin and quantitated as the debrisoquin recovery ratio (DBRR) 20 . We have also shown that concentrations of mRNA for CYP2D6 in bladder mucosa were associated with the DBRR in patients with bladder cancer 17 . Thus there is preliminary evidence for coordinated regulation between hepatic and extrahepatic sites for this enzyme.…”

CYP4B1 Is a Possible Risk Factor for Bladder Cancer in Humans

“…In the bladder-tumor patients, CYP4B1 expression in the normal region of the bladder was not significantly different from that of the tumor region. Romkes-Sparks et al (15) have reported an association between CYP2D6 mRNA levels and human bladder cancer. CYP2D6 levels were also assayed by real-time PCR.…”