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) [1α,25(OH)(2)D(3)]. Hepatic biotransformation of 1α,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 1α,25(OH)(2)D(3) in mouse and human liver microsomes and determined the effects of commonly used drugs on the catabolism of 1α,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 1α,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 1α,25(OH)(2)D(3) in MLM. Coincubation of 1α,25(OH)(2)D(3) with commonly used drugs led to approximately 60 to 100% inhibition of CYP3A4-mediated catabolism of 1α,25-(OH)(2)D(3) in HLM. A species-based difference was identified between CYP3A-mediated hepatic microsomal metabolism of 1α,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.
The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6.
Subrata
S
Deb
Mitali
M
Pandey
Hans
H
Adomat
Emma S Tomlinson
ES
Guns
D000818:Animals; D002117:Calcitriol / Q000378:metabolism* / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D011241:Prednisone / Q000494:pharmacology; D013045:Species Specificity; D008565:Membrane Proteins
D002117:Calcitriol; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D003907:Dexamethasone; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D011241:Prednisone; C104464:CYP3A protein, human; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins