An Inducible Cytochrome P450 3A4-Dependent Vitamin D Catabolic Pathway

作者：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^*

来源：Molecular Pharmacology, 2012, 81(4): 498-509.

DOI：10.1124/mol.111.076356

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 4 beta,25-dihydroxyvitamin D-3 [4 beta,25(OH)(2)D-3] dominating (V-max/K-m = 0.85 ml . min(-1) . nmol enzyme(-1)). 4 beta,25(OH)(2)D-3 was found in human plasma at concentrations comparable to that of 1 alpha,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 4 beta,25(OH)(2)D-3 in primary human hepatocytes was induced by rifampin and inhibited by CYP3A4-specific inhibitors. Shortterm treatment of healthy volunteers (n = 6) with rifampin selectively induced CYP3A4-dependent 4 beta,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.

• 出版日期2012-4