Title: An inducible cytochrome P450 3A4-dependent vitamin D catabolic pathway.

Authors: Wang, Zhican; Lin, Yvonne S; Zheng, Xi Emily; Senn, Tauri; Hashizume, Takanori; Scian, Michele; Dickmann, Leslie J; Nelson, Sidney D; Baillie, Thomas A; Hebert, Mary F; Blough, David; Davis, Connie L; Thummel, Kenneth E

Published In Mol Pharmacol, (2012 Apr)

Abstract: Vitamin D(3) is critical for the regulation of calcium and phosphate homeostasis. In some individuals, mineral homeostasis can be disrupted by long-term therapy with certain antiepileptic drugs and the antimicrobial agent rifampin, resulting in drug-induced osteomalacia, which is attributed to vitamin D deficiency. We now report a novel CYP3A4-dependent pathway, the 4-hydroxylation of 25-hydroxyvitamin D(3) (25OHD(3)), the induction of which may contribute to drug-induced vitamin D deficiency. The metabolism of 25OHD(3) was fully characterized in vitro. CYP3A4 was the predominant source of 25OHD(3) hydroxylation by human liver microsomes, with the formation of 4ýý,25-dihydroxyvitamin D(3) [4ýý,25(OH)(2)D(3)] dominating (V(max)/K(m) = 0.85 ml ýý min(-1) ýý nmol enzyme(-1)). 4ýý,25(OH)(2)D(3) was found in human plasma at concentrations comparable to that of 1ýý,25-dihydroxyvitamin D(3), and its formation rate in a panel of human liver microsomes was strongly correlated with CYP3A4 content and midazolam hydroxylation activity. Formation of 4ýý,25(OH)(2)D(3) in primary human hepatocytes was induced by rifampin and inhibited by CYP3A4-specific inhibitors. Short-term treatment of healthy volunteers (n = 6) with rifampin selectively induced CYP3A4-dependent 4ýý,25(OH)(2)D(3), but not CYP24A1-dependent 24R,25-dihydroxyvitamin D(3) formation, and altered systemic mineral homeostasis. Our results suggest that CYP3A4-dependent 25OHD(3) metabolism may play an important role in the regulation of vitamin D(3) in vivo and in the etiology of drug-induced osteomalacia.

PubMed ID: 22205755

MeSH Terms: No MeSH terms associated with this publication