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

Osteomalacia Hydroxylation
DOI: 10.1124/mol.111.076356 Publication Date: 2011-12-29T03:21:47Z
ABSTRACT
Vitamin D<sub>3</sub> 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 (25OHD<sub>3</sub>), induction may contribute The metabolism 25OHD<sub>3</sub> was fully characterized vitro. CYP3A4 predominant source hydroxylation human liver microsomes, formation 4β,25-dihydroxyvitamin [4β,25(OH)<sub>2</sub>D<sub>3</sub>] dominating (<i>V</i><sub>max</sub>/<i>K</i><sub>m</sub> = 0.85 ml · min<sup>−1</sup> nmol enzyme<sup>−1</sup>). 4β,25(OH)<sub>2</sub>D<sub>3</sub> found plasma at concentrations comparable that 1α,25-dihydroxyvitamin D<sub>3</sub>, 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)<sub>2</sub>D<sub>3</sub>, but not CYP24A1-dependent 24<i>R</i>,25-dihydroxyvitamin formation, altered systemic Our results suggest play an important role vivo etiology osteomalacia.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (40)
CITATIONS (96)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....