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,25-Dihydroxyvitamin D3: Implications for Drug-Induced Osteomalacia
Department of Pharmaceutics (Y.X., T.H., K.E.T.), Divisions of Gastroenterology (M.C.S.) and Nephrology (C.L.D.), Department of Medicine, and Department of Medicinal Chemistry (W.L.N., T.F.K.), University of Washington, Seattle, Washington; Biotechnology Research Center, Toyama Prefectural University, Izumi-gun, Toyama, Japan (T.S.); Division of Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina (P.B.W.); and St. Jude Children's Research Hospital, Memphis, Tennessee (E.G.S.)
The decline in bone mineral density that occurs after long-term treatment with some antiepileptic drugs is thought to be mediated by increased vitamin D3 metabolism. In this study, we show that the inducible enzyme CYP3A4 is a major source of oxidative metabolism of 1
,25-dihydroxyvitamin D3 [1,25(OH)2D3] in human liver and small intestine and could contribute to this adverse effect. Heterologously-expressed CYP3A4 catalyzed the 23- and 24-hydroxylation of 1,25(OH)2D3. No human microsomal cytochrome P450 enzyme tested, other than CYP3A5, supported these reactions. CYP3A4 exhibited opposite product stereochemical preference compared with that of CYP24A1, a known 1,25(OH)2D3 hydroxylase. The three major metabolites generated by CYP3A4 were 1,23R,25(OH)3D3, 1,24S,25(OH)3D3, and 1,23S,25(OH)3D3. Although the metabolic clearance of CYP3A4 was less than that of CYP24A1, comparison of metabolite profiles and experiments using CYP3A-specific inhibitors indicated that CYP3A4 was the dominant source of 1,25(OH)2D3 23- and 24-hydroxylase activity in both human small intestine and liver. Consistent with this observation, analysis of mRNA isolated from human intestine and liver (including samples from donors treated with phenytoin) revealed a general absence of CYP24A1 mRNA. In addition, expression of CYP3A4 mRNA in a panel of duodenal samples was significantly correlated with the mRNA level of a known vitamin D receptor gene target, calbindin-D9K. These and other data suggest that induction of CYP3A4-dependent 1,25(OH)2D3 metabolism by antiepileptic drugs and other PXR ligands may diminish intestinal effects of the hormone and contribute to osteomalacia.
Address correspondence to: Dr. Kenneth E. Thummel, Department of Pharmaceutics, Box 357610, University of Washington, Seattle, WA 98195-7610. E-mail: thummel{at}u.washington.edu
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