title: Regulation of CYP3A4 and CYP3A5 expression and modulation of "intracrine" metabolism of androgens in prostate cells by liganded vitamin D receptor.
abstract: We investigated the capacity for vitamin D receptor (VDR) to modulate the expression of CYP3A4 and other genes that may facilitate the oxidative inactivation of androgens such as testosterone and androstanediol within prostate cells. We report that exposure to the active hormonal form of vitamin D markedly increased gene expression of CYP3A4 and CYP3A5 and ultimately achieved levels of intracellular CYP3A enzyme activity within LNCaP prostate cancer cells that were comparable to that observed for Caco2 cells, an established model of CYP3A induction, and resulted in the increased turnover of testosterone to its inactive 6β-OH metabolite. We demonstrate that VDR directs CYP3A4 and CYP3A5 expression through binding to distinct regulatory motifs located within the 5' promoter regions of both genes. The current data highlight the potential application of VDR-based treatment regimes as a means to limit the bioavailability of growth-promoting androgens within the tumor microenvironment.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, Ireland.
authors.forename: Orla
authors.initials: O
authors.lastname: Maguire
authors.forename: Catherine
authors.initials: C
authors.lastname: Pollock
authors.forename: Philip
authors.initials: P
authors.lastname: Martin
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.forename: Thomas
authors.initials: T
authors.lastname: Smyth
authors.forename: Declan
authors.initials: D
authors.lastname: Doherty
authors.forename: Moray J
authors.initials: MJ
authors.lastname: Campbell
authors.forename: Stephen
authors.initials: S
authors.lastname: McClean
authors.forename: Paul
authors.initials: P
authors.lastname: Thompson
mesh_terms: D015114:Androstenediol / Q000378:metabolism*; D018938:Caco-2 Cells; D002117:Calcitriol / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D042926:Cytochrome P-450 CYP4A / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008297:Male; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism*; D014162:Transfection
chemical_list: D008024:Ligands; D018167:Receptors, Calcitriol; D013739:Testosterone; D015114:Androstenediol; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D042926:Cytochrome P-450 CYP4A; D002117:Calcitriol