Cytochrome P450 CYP1B1 activity in renal cell carcinoma.
Renal cell carcinoma (RCC) is the most common malignancy of the kidney and has a poor prognosis due to its late presentation and resistance to current anticancer drugs. One mechanism of drug resistance, which is potentially amenable to therapeutic intervention, is based on studies in our laboratory. CYP1B1 is a cytochrome P450 enzyme overexpressed in a variety of malignant tumours. Our studies are now elucidating a functional role for CYP1B1 in drug resistance. Cytochrome P450 reductase (P450R) is required for optimal metabolic activity of CYP1B1. Both CYP1B1 and P450R can catalyse the biotransformation of anticancer drugs at the site of the tumour. In this investigation, we determined the expression of CYP1B1 and P450R in samples of normal kidney and RCC (11 paired normal and tumour and a further 15 tumour samples). The O-deethylation of ethoxyresorufin to resorufin was used to measure CYP1B1 activity in RCC. Cytochrome P450 reductase activity was determined by following the reduction of cytochrome c at 550 nm. The key finding of this study was the presence of active CYP1B1 in 70% of RCC. Coincubation with the CYP1B1 inhibitor alpha-naphthoflavone (10 nM) inhibited this activity. No corresponding CYP1B1 activity was detected in any of the normal tissue examined (n=11). Measurable levels of active P450R were determined in all normal (n=11) and tumour samples (n=26). The presence of detectable CYP1B1, which is capable of metabolising anticancer drugs in tumour cells, highlights a novel target for therapeutic intervention.
Department of Pathology, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. m.mcfadyen@abdn.ac.uk
M C E
MC
McFadyen
W T
WT
Melvin
G I
GI
Murray
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism*; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D010078:Oxazines / Q000378:metabolism
D004791:Enzyme Inhibitors; D010078:Oxazines; C007649:ethoxyresorufin; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D009251:NADPH-Ferrihemoprotein Reductase