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Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D(3) through CYP3A4 induction in vitro and in vivo: Implications for drug-induced osteomalacia.


J Bone Miner Res. 2012 Dec 4;


Authors: Wang Z, Lin YS, Dickmann LJ, Poulton EJ, Eaton DL, Lampe JW, Shen DD, Davis CL, Shuhart MC, Thummel KE


Abstract

Long-term therapy with certain drugs, especially P450 inducing agents, confers an increased risk of osteomalacia that is attributed to vitamin D deficiency. Human CYP24A1, CYP3A4 and CYP27B1 catalyze the inactivation and activation of vitamin D and have been implicated in the adverse drug response. In this study, the inducibility of these enzymes and monohydroxylation of 25OHD(3) were evaluated following exposure to P450 inducing drugs. With human hepatocytes, treatment with phenobarbital, hyperforin, carbamazepine and rifampin significantly increased the levels of CYP3A4 but not CYP24A1 or CYP27B1 mRNA. In addition, rifampin pretreatment resulted in an 8-fold increase in formation of the major metabolite of 25OHD(3) , 4β,25(OH)(2) D(3) . This inductive effect was blocked by the addition of 6',7'-dihydroxybergamottin, a selective CYP3A4 inhibitor. With human renal proximal tubular HK-2 cells, treatment with the same inducers did not alter CYP3A4, CYP24A1 or CYP27B1 expression. 24R,25(OH)(2) D(3) was the predominant monohydroxy metabolite produced from 25OHD(3) , but its formation was unaffected by the inducers. With healthy volunteers, the mean plasma concentration of 4β,25(OH)(2) D(3) was increased 60% (p < 0.01) after short-term rifampin administration. This was accompanied by a statistically significant reduction in plasma 1α,25(OH)(2) D(3) (-10%; p = 0.03), and a non-significant change in 24R,25(OH)(2) D(3) (-8%; p = 0.09) levels. Further analysis revealed a negative correlation between the increase in 4β,25(OH)(2) D(3) and decrease in 1α,25(OH)(2) D(3) levels. Examination of the plasma monohydroxy metabolite/25OHD(3) ratios indicated selective induction of the CYP3A4-dependent 4β-hydroxylation pathway of 25OHD(3) elimination. These results suggest that induction of hepatic CYP3A4 may be important in the etiology of drug-induced osteomalacia. © 2012 American Society for Bone and Mineral Research.

PMID: 23212742 [PubMed - as supplied by publisher]