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Carcinogenesis Advance Access originally published online on November 20, 2006
Carcinogenesis 2007 28(5):916-921; doi:10.1093/carcin/bgl222
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Characterization of androgen-regulated expression of CYP3A5 in human prostate

Anne-Mari Moilanen, Jukka Hakkola2, Markku H. Vaarala1,*, Saila Kauppila, Pasi Hirvikoski, Jussi T. Vuoristo3, Robert J. Edwards4 and Timo K. Paavonen5

Department of Pathology, University of Oulu and University Hospital of Oulu, FIN-90014 Oulu, Finland
1 Department of Surgery, University of Oulu and University Hospital of Oulu, PO Box 21, FIN-90029 OYS, Oulu, Finland
2 Department of Pharmacology and Toxicology, University of Oulu, FIN-90014 Oulu, Finland
3 Biocenter Oulu, FIN-90014 Oulu, Finland
4 Section on Experimental Medicine and Toxicology, Imperial College London, London, WC2A 3PX, UK
5 Department of Pathology, University of Tampere, FIN-33014 Tampere, Finland

* To whom correspondence should be addressed. Tel: +358 8 315 2840; Fax: +358 8 315 2004; Email: markku.vaarala{at}oulu.fi

Testosterone is needed for the growth and development of the prostate. Androgen deprivation therapy is used for the treatment of prostate cancer. CYP3A5 is a human drug-metabolizing cytochrome P450 enzyme that metabolizes testosterone to the inactive 6ß-hydroxylated metabolite. We identified CYP3A5 as a novel androgen-regulated gene in human prostate by GeneChip analysis of human prostate tissues obtained from patients 3 days after therapeutic castration and from control patients. We further showed androgen induction of CYP3A5 messenger RNA (mRNA) in LNCaP prostate cancer cell line. Immunoblotting studies revealed CYP3A5 protein expression in all prostate samples studied. Immunohistochemistry and in situ hybridization was used for localization of CYP3A5 expression in prostate tissue. CYP3A5 was detected both in luminal and in basal epithelial cells of human prostate. Androgen response element was identified in the CYP3A5 proximal promoter and in electrophoretic mobility shift assay androgen receptor was found to bind this element. Androgen induction was abolished by mutation of the response element. We suggest that CYP3A5 is a part of an autoregulatory feedback loop controlling prostate cell exposure to androgens.

Abbreviations: AR, androgen receptor; ARE, androgen response element; CYP, cytochrome P450; mRNA, messenger RNA; RT–PCR, reverse transcription–polymerase chain reaction

Received August 11, 2006; revised November 6, 2006; accepted November 6, 2006.


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