کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2514824 | 1118487 | 2008 | 12 صفحه PDF | دانلود رایگان |
P-glycoprotein, encoded by the multidrug resistance 1 (MDR1) gene, is an efflux transporter and plays an important role in pharmacokinetics. The expression of MDR1 is induced by a variety of compounds, of which 1α,25-dihydroxyvitamin D3 is known to be an effective inducer. However, it remains unclear how 1α,25-dihydroxyvitamin D3 regulates the expression of MDR1. In this study, we demonstrated that the vitamin D receptor (VDR) induces MDR1 expression in a 1α,25-dihydroxyvitamin D3-dependent manner. Luciferase assays revealed that the region between −7.9 and −7.8 kbp upstream from the transcription start site of the MDR1 is responsible for the induction by 1α,25-dihydroxyvitamin D3. Electrophoretic mobility shift assays revealed that several binding sites for the VDR/retinoid X receptor α (RXRα) heterodimer are located between the −7880 and −7810 bp region, to which the three molecules of VDR/RXRα are able to simultaneously bind with different affinities. Luciferase assays using mutated constructs revealed that the VDR-binding sites of DR3, DR4(I), MdC3, and DR4(III) contribute to the induction, indicating that these binding sites act as vitamin D response elements (VDREs). The contribution of each VDRE to the inducibility was different for each response element. An additive effect of the individual VDREs on induced luciferase activity by 1α,25-dihydroxyvitamin D3 was also observed. These results indicate that the induction of MDR1 by 1α,25-dihydroxyvitamin D3 is mediated by VDR/RXRα binding to several VDREs located between −7880 and −7810 bp, in which every VDRE additively contributes to the 1α,25-dihydroxyvitamin D3 response.
Journal: Biochemical Pharmacology - Volume 76, Issue 4, 15 August 2008, Pages 531–542