Cytochrome P450 3A-Mediated Microsomal Biotransformation of 1α,25-Dihydroxyvitamin D3 in Mouse and Human Liver: Drug-Related Induction and Inhibition of Catabolism

The biological activities of vitamin D-3 are exerted through the dihydroxy metabolite of vitamin D-3 [1 alpha,25(OH)(2)D-3]. Hepatic biotransformation of 1 alpha,25(OH)(2)D-3 by cytochrome P450 (P450) enzymes could be an important determinant of bioavailability in serum and tissues. In the present study, we investigated the comparative biotransformation of 1 alpha,25(OH)(2)D-3 in mouse and human liver microsomes and determined the effects of commonly used drugs on the catabolism of 1 alpha,25(OH)(2)D-3. Severe symptoms of vitamin D deficiency have historically been observed in patients who received dexamethasone. To compare the effects of clinically important glucocorticoids with hepatic biotransformation of 1 alpha,25(OH)(2)D-3, adult male CD-1 mice were given intraperitoneal injections of either vehicle (50% ethanol), dexamethasone (80 mg/kg per day), or prednisone (80 mg/kg per day) for three consecutive days. Hydroxy metabolite formation pattern and the extent of substrate depletion were similar in mouse liver microsomes (MLM) from vehicle-or prednisone-treated mice, whereas treatment with dexamethasone led to the emergence of additional metabolites and increased substrate depletion, as determined by liquid chromatography/mass spectrometry. The metabolite formation profile in vehicle-treated mice was different from that of human liver microsomes (HLM). Selective P450 chemical inhibitors have demonstrated that CYP3A isoforms are responsible for the microsomal biotransformation of 1 alpha,25(OH)(2)D-3 in MLM. Coincubation of 1 alpha,25(OH)(2)D-3 with commonly used drugs led to approximately 60 to 100% inhibition of CYP3A4-mediated catabolism of 1 alpha,25(OH)(2)D-3 in HLM. A species-based difference was identified between CYP3A-mediated hepatic microsomal metabolism of 1 alpha,25(OH)(2)D-3 in humans and mice. We have shown that the clinical importance of glucocorticoids differentially modulates catabolism of active vitamin D-3 and that commonly used drugs could affect vitamin D homeostasis.