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

• DOI: 10.1124/mol.111.076356
• Publication Date: 2011-12-29T03:21:47Z
• Authors: Zhican Wang; Yvonne S. Lin; Xi Emily Zheng; Tauri Senn; Takanori Hashizume; Michele Scian; Leslie J. Dickmann; Sidney D. Nelson; Thomas A. Baillie; Mary F. Hebert; David Blough; Connie L. Davis; Kenneth E. Thummel
• Keywords: 0301 basic medicine; 0303 health sciences; 03 medical and health sciences; Tandem Mass Spectrometry; Microsomes, Liver; Cytochrome P-450 CYP3A; Humans; Vitamin D; Chromatography, High Pressure Liquid; 3. Good health

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 4β,25-dihydroxyvitamin D(3) [4β,25(OH)(2)D(3)] dominating (V(max)/K(m) = 0.85 ml · min(-1) · nmol enzyme(-1)). 4β,25(OH)(2)D(3) was found in human plasma at concentrations comparable to that of 1α,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 4β,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 4β,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.