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: Osteomalacia; Hydroxylation

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 antimicrobial agent rifampin, resulting in drug-induced osteomalacia, which attributed to vitamin D deficiency. We now report a novel CYP3A4-dependent pathway, 4-hydroxylation 25-hydroxyvitamin (25OHD₃), induction may contribute The metabolism 25OHD₃ was fully characterized vitro. CYP3A4 predominant source hydroxylation human liver microsomes, formation 4β,25-dihydroxyvitamin [4β,25(OH)₂D₃] dominating (<i>V</i>_max/<i>K</i>_m = 0.85 ml · min⁻¹ nmol enzyme⁻¹). 4β,25(OH)₂D₃ found plasma at concentrations comparable that 1α,25-dihydroxyvitamin D₃, its rate panel microsomes strongly correlated content midazolam activity. Formation primary hepatocytes induced rifampin inhibited CYP3A4-specific inhibitors. Short-term treatment healthy volunteers (<i>n</i> 6) selectively 4β,25(OH)₂D₃, but not CYP24A1-dependent 24<i>R</i>,25-dihydroxyvitamin formation, altered systemic Our results suggest play an important role vivo etiology osteomalacia.