PT  - JOURNAL ARTICLE
AU  - Zhican Wang
AU  - Yvonne S. Lin
AU  - Xi Emily Zheng
AU  - Tauri Senn
AU  - Takanori Hashizume
AU  - Michele Scian
AU  - Leslie J. Dickmann
AU  - Sidney D. Nelson
AU  - Thomas A. Baillie
AU  - Mary F. Hebert
AU  - David Blough
AU  - Connie L. Davis
AU  - Kenneth E. Thummel
TI  - An Inducible Cytochrome P450 3A4-dependent Vitamin D Catabolic Pathway
AID  - 10.1124/mol.111.076356
DP  - 2011 Dec 28
TA  - Molecular Pharmacology
PG  - mol.111.076356
4099  - http://molpharm.aspetjournals.org/content/early/2011/12/28/mol.111.076356.short
4100  - http://molpharm.aspetjournals.org/content/early/2011/12/28/mol.111.076356.full
AB  - Vitamin D3 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 D3 (25OHD3), the induction of which may contribute to drug-induced vitamin D deficiency. The metabolism of 25OHD3 was fully characterized in vitro. CYP3A4 was the predominant source of 25OHD3 hydroxylation by human liver microsomes, with the formation of 4β,25(OH)2D3 dominating (Vmax/Km = 1.32 ml/min/nmol enzyme). 4β,25(OH)2D3 was found in human plasma at concentrations comparable to that of 1α,25(OH)2D3, 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)2D3 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)2D3, but not CYP24A1-dependent 24R,25(OH)2D3 formation, and altered systemic mineral homeostasis. Our results suggest that CYP3A4-dependent 25OHD3 metabolism may play an important role in the regulation of vitamin D3 in vivo and in the etiology of drug-induced osteomalacia.