An Inducible Cytochrome P450 3A4-Dependent Vitamin D Catabolic Pathway
| Autor: | Thomas A. Baillie, Zhican Wang, Takanori Hashizume, Mary F. Hebert, Yvonne S. Lin, David K. Blough, Leslie J. Dickmann, Sidney D. Nelson, Connie L. Davis, Tauri Senn, Michele Scian, Kenneth E. Thummel, Xi Emily Zheng |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Vitamin
medicine.medical_specialty chemistry.chemical_element Pharmacology Calcium vitamin D deficiency Hydroxylation chemistry.chemical_compound Tandem Mass Spectrometry Internal medicine medicine Vitamin D and neurology Cytochrome P-450 CYP3A Humans Vitamin D Chromatography High Pressure Liquid Osteomalacia CYP3A4 Chemistry Articles medicine.disease Endocrinology Microsomes Liver Microsome Molecular Medicine |
| Zdroj: | Molecular Pharmacology. 81:498-509 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.111.076356 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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