title: Abiraterone inhibits 1α,25-dihydroxyvitamin D3 metabolism by CYP3A4 in human liver and intestine in vitro.
abstract: The chemopreventive and therapeutic effects of vitamin D3 are exerted through its dihydroxylated metabolite, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3]. Inactivation of 1α,25(OH)2D3 by cytochrome P450 3A4 (CYP3A4) may be an important determinant of its serum and tissue levels. Abiraterone, a steroidogenesis inhibitor used in late stage prostate cancer treatment, is a CYP17A1 inhibitor. The purpose of this study was to assess the potential of abiraterone to block hepatic and intestinal inactivation of biologically active vitamin D3in vitro and to evaluate if abiraterone can alter CYP3A4 marker substrate activities. Biotransformation reactions were initiated with NADPH regenerating solutions following initial preincubation of pooled human hepatic or intestinal microsomal protein or human recombinant CYP3A4 supersomes with 1α,25(OH)2D3, midazolam or triazolam for 10min at 37°C. Formation of hydroxylated metabolites of 1α,25(OH)2D3, midazolam or triazolam was analyzed by liquid chromatography-mass spectrometry method. Co-incubation of 1α,25(OH)2D3 with abiraterone at varying concentrations (0.2-100μM) led to up to ∼85% inhibition of formation of hydroxylated metabolites of 1α,25(OH)2D3 thus preventing inactivation of active vitamin D3. The IC50 values for individual metabolites of 1α,25(OH)2D3 ranged from 0.4 to 2.2μM in human liver microsomes or human intestinal microsomes. The mechanism of CYP3A4-mediated inhibition of 1α,25(OH)2D3 by abiraterone was competitive (apparent Ki 2.8-4.3μM). Similar inhibitory effects were also observed upon inclusion of abiraterone into midazolam or triazolam hydroxylation assays. In summary, our results suggest that abiraterone inhibits the CYP3A4-mediated inactivation of active vitamin D3 in human liver and intestine, potentially providing additional anti-cancer benefits to prostate cancer patients. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.
authors.affiliation: The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC, Canada V6H 3Z6.
authors.forename: Subrata
authors.initials: S
authors.lastname: Deb
authors.affiliation: The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC, Canada V6H 3Z6.
authors.forename: Mei Yieng
authors.initials: MY
authors.lastname: Chin
authors.affiliation: The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC, Canada V6H 3Z6.
authors.forename: Hans
authors.initials: H
authors.lastname: Adomat
authors.affiliation: The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC, Canada V6H 3Z6. Electronic address: eguns@prostatecentre.com.
authors.forename: Emma S Tomlinson
authors.initials: ES
authors.lastname: Guns
mesh_terms: D000736:Androstenes; D000737:Androstenols / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D000736:Androstenes; D000737:Androstenols; D065692:Cytochrome P-450 CYP3A Inhibitors; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C089740:abiraterone
keywords: Abiraterone; CYP3A4; Inhibition; Interaction; Microsomes; Vitamin D(3)