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Cytochrome P450 CYP1B1 activity in renal cell carcinoma.

McFadyen, M.C.E.; Melvin, W.T.; Murray, G.I.

Authors

M.C.E. McFadyen

W.T. Melvin

G.I. Murray



Abstract

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 (10nM) 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.

Citation

MCFADYEN, M.C.E., MELVIN, W.T. and MURRAY, G.I. 2004. Cytochrome P450 CYP1B1 activity in renal cell carcinoma. British journal of cancer [online], 91, pages 966-971. Available from: https://doi.org/10.1038/sj.bjc.6602053

Journal Article Type Article
Acceptance Date Jun 7, 2004
Online Publication Date Jul 27, 2004
Publication Date Aug 31, 2004
Deposit Date Jun 18, 2020
Publicly Available Date Jun 18, 2020
Journal British journal of cancer
Print ISSN 0007-0920
Electronic ISSN 1532-1827
Publisher Springer
Peer Reviewed Peer Reviewed
Volume 91
Issue 5
Pages 966-971
DOI https://doi.org/10.1038/sj.bjc.6602053
Keywords CYP1B1; Cytochrome P450 reductase; Renal cell carcinoma; Therapeutic intervention; Tumours
Public URL https://rgu-repository.worktribe.com/output/820251

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