Human PXR-mediated induction of intestinal CYP3A4 attenuates 1伪,25-dihydroxyvitamin D₃ function in human colon adenocarcinoma LS180 cells

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• 作者：Xi Emily Zheng^a ; ¹ ; Zhican Wang^a ; Michael Z. Liao^a ; Yvonne S. Lin^a ; Margaret C. Shuhart^b ; Erin G. Schuetz^c ; Kenneth E. Thummel^a ; ^{thummel@u.washington.edu}
• 关键词：Cytochrome P450 3A4 ; TRPV6 ; 1伪 ; 25-Dihydroxyvitamin D3 ; Human pregnane X receptor ; Rifampin ; Osteomalacia
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 期刊代码：2_00062952
• 类别：pha
• 出版时间：1 August, 2012
• 卷：84
• 期：3
• 页码：391-401
• 文件大小：995 K

摘要

Oxidative catabolism of 1伪,25-dihydroxyvitamin D₃ [1伪,25(OH)₂D₃] is mediated by either CYP24A1 or CYP3A4. In this paper, we tested whether induction of CYP3A4 in the LS180 intestinal cell model enhances clearance of 1伪,25(OH)₂D₃ and blunts its hormonal effect on expression of the apical membrane calcium transport protein, TRPV6. Treatment with the hPXR agonist rifampin significantly increased CYP3A4 mRNA content and catalytic activity, but had no effect on CYP24A1 or TRPV6 mRNA content. Pre-treating cells with rifampin for 48 h, prior to a 24 h 1伪,25(OH)₂D₃ treatment phase, was associated with a subsequent 48%increase in the elimination of 1伪,25(OH)₂D₃ and a 35%reduction of peak TRPV6 mRNA. Introduction of the CYP3A4 inhibitor, 6鈥?7鈥?dihydroxybergamottin, an active inhibitor in grapefruit juice, reversed the effects of rifampin on 1伪,25(OH)₂D₃ clearance and TRPV6 expression. Over-expression of hPXR in LS180 cells greatly enhanced the CYP3A4 responsiveness to rifampin pretreatment, and elicited a greater relative suppression of TRPV6 expression and an increase in 1伪,25(OH)₂D₃ disappearance rate, compared to vector expressed cells, following hormone administration. Together, these results suggest that induction of CYP3A4 in the intestinal epithelium by hPXR agonists can result in a greater metabolic clearance of 1伪,25(OH)₂D₃ and reduced effects of the hormone on the intestinal calcium absorption, which may contribute to an increased risk of drug-induced osteomalacia/osteoporosis in patients receiving chronic therapy with potent hPXR agonists. Moreover, ingestion of grapefruit juice in the at-risk patients could potentially prevent this adverse drug effect.