Baker, Simon C. and Arlt, Volker M. and Indra, Radek and Joel, Madeleine and Stiborova, Marie and Eardley, Ian and Ahmad, Niaz and Otto, Wolfgang and Burger, Maximilian and Rubenwolf, Peter and Phillips, David H. and Southgate, Jennifer (2018) Differentiation-associated urothelial cytochrome P450 oxidoreductase predicates the xenobiotic-metabolizing activity of "luminal" muscle-invasive bladder cancers. MOLECULAR CARCINOGENESIS, 57 (5). pp. 606-618. ISSN 0899-1987, 1098-2744
Full text not available from this repository. (Request a copy)Abstract
Extra-hepatic metabolism of xenobiotics by epithelial tissues has evolved as a self-defence mechanism but has potential to contribute to the local activation of carcinogens. Bladder epithelium (urothelium) is bathed in excreted urinary toxicants and pro-carcinogens. This study reveals how differentiation affects cytochrome P450 (CYP) activity and the role of NADPH:P450 oxidoreductase (POR). CYP1A1 and CYP1B1 transcripts were inducible in normal human urothelial (NHU) cells maintained in both undifferentiated and functional barrier-forming differentiated states in vitro. However, ethoxyresorufin O-deethylation (EROD) activity, the generation of reactive BaP metabolites and BaP-DNA adducts, were predominantly detected in differentiated NHU cell cultures. This gain-of-function was attributable to the expression of POR, an essential electron donor for all CYPs, which was significantly upregulated as part of urothelial differentiation. Immunohistology of muscle-invasive bladder cancer (MIBC) revealed significant overall suppression of POR expression. Stratification of MIBC biopsies into luminal and basal groups, based on GATA3 and cytokeratin 5/6 labeling, showed POR over-expression by a subgroup of the differentiated luminal tumors. In bladder cancer cell lines, CYP1-activity was undetectable/low in basal PORlo T24 and SCaBER cells and higher in the luminal POR over-expressing RT4 and RT112 cells than in differentiated NHU cells, indicating that CYP-function is related to differentiation status in bladder cancers. This study establishes POR as a predictive biomarker of metabolic potential. This has implications in bladder carcinogenesis for the hepatic versus local activation of carcinogens and as a functional predictor of the potential for MIBC to respond to prodrug therapies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | IN-VITRO; P450 OXIDOREDUCTASE; DNA-ADDUCTS; ANTITUMOR AGENTS; RISK; RECEPTOR; TISSUE; CELLS; DRUG; BENZO(A)PYRENE; aryl hydrocarbon receptor; CPR; CYP1A1; POR; urothelium |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Urologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Mar 2020 15:04 |
| Last Modified: | 19 Mar 2020 15:04 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14699 |
Actions (login required)
 |
View Item |
