Abiraterone inhibits 1α,25-dihydroxyvitamin D3 metabolism by CYP3A4 in human liver and intestine in vitro

The chemopreventive and therapeutic effects of vitamin D-3 are exerted through its dihydroxylated metabolite, 1 alpha,25-dihydroxyvitamin D-3 [1 alpha,25(OH)(2)D-3]. Inactivation of 1 alpha,25(OH)(2)D-3 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 D3 in 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 1 alpha,25(OH)(2)D-3, midazolam or triazolam for 10 min at 37 degrees C, Formation of hydroxylated metabolites of 1 alpha,25(OH)(2)D-3, midazolam or triazolam was analyzed by liquid chromatography-mass spectrometry method. Co-incubation of 1 alpha,25(OH)(2)D-3 with abiraterone at varying concentrations (0.2-100 mu M) led to up to similar to 85% inhibition of formation of hydroxylated metabolites of 1 alpha,25(OH)(2)D-3 thus preventing inactivation of active vitamin D3. The IC50 values for individual metabolites of 1 alpha,25(OH)(2)D-3 ranged from 0.4 to 2.2 mu M in human liver microsomes or human intestinal microsomes. The mechanism of CYP3A4-mediated inhibition of 1 alpha,25(OH)(2)D-3 by abiraterone was competitive (apparent K-i 2.8-4.3 mu M). 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'. (C) 2013 Published by Elsevier Ltd.