Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human multidrug resistance gene MDR3 encodes a P-glycoprotein that belongs to the ATP-binding cassette transporter family (ABCB4). MDR3 is a critical trans-locator for phospholipids across canalicular membranes of hepatocytes, evidenced by the fact that human MDR3 deficiencies result in progressive familial intrahepatic cholestasis type III. It has been reported previously that MDR3 expression is modulated by hormones, cellular stress, and xenobiotics. Here we show that the MDR3 gene is trans-activated by the farnesoid X receptor (FXR) via a direct binding of FXR/retinoid X receptor alpha heterodimers to a highly conserved inverted repeat element (a FXR response element) at the distal promoter (-1970 to -1958). In FXR trans-activation assays, both the endogenous FXR agonist chenodeoxycholate and the synthetic agonist GW4064 activated the MDR3 promoter. Deletion or mutation of this inverted repeat element abolished FXR-mediated MDR3 promoter activation. Consistent with these data, MDR3 mRNA was significantly induced by both chenodeoxycholate and GW4064 in primary human hepatocytes in time- and dose-dependent fashions. In conclusion, we demonstrate that MDR3 expression is directly up-regulated by FXR. These results, together with the previous report that the bile salt export pump is a direct FXR target, suggest that FXR coordinately controls secretion of bile salts and phospholipids. Results of this study further support the notion that FXR is a master regulator of lipid metabolism.
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PMID:Farnesoid X receptor activates transcription of the phospholipid pump MDR3. 1452 55

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 1alpha,25-dihydroxyvitamin D(3) is known to be an effective inducer. However, it remains unclear how 1alpha,25-dihydroxyvitamin D(3) regulates the expression of MDR1. In this study, we demonstrated that the vitamin D receptor (VDR) induces MDR1 expression in a 1alpha,25-dihydroxyvitamin D(3)-dependent manner. Luciferase assays revealed that the region between -7.9 and -7.8k bp upstream from the transcription start site of the MDR1 is responsible for the induction by 1alpha,25-dihydroxyvitamin D(3). Electrophoretic mobility shift assays revealed that several binding sites for the VDR/retinoid X receptor alpha (RXRalpha) heterodimer are located between the -7880 and -7810 bp region, to which the three molecules of VDR/RXRalpha 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 1alpha,25-dihydroxyvitamin D(3) was also observed. These results indicate that the induction of MDR1 by 1alpha,25-dihydroxyvitamin D(3) is mediated by VDR/RXRalpha binding to several VDREs located between -7880 and -7810bp, in which every VDRE additively contributes to the 1alpha,25-dihydroxyvitamin D(3) response.
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PMID:Identification of the functional vitamin D response elements in the human MDR1 gene. 1860 86

ABCB1 (P-glycoprotein) is an efflux transporter that limits the cellular uptake levels of various drugs in intestine, brain, and other tissues. The expression of human ABCB1 has recently been reported to be under the control of nuclear receptor NR1I subfamily members, pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3). Here, we have investigated the involvement of another NR1I member, vitamin D receptor (VDR, NR1I1), in ABCB1 expression. In the human colorectal adenocarcinoma cell line LS174T, which abundantly expresses VDR, both 1alpha,25-dihydroxyvitamin D(3) (1,25-VD3) and lithocholic acid (LCA) increased ABCB1 mRNA levels. Reporter gene assays in LS174T cells with constructs containing various lengths of the ABCB1 regulatory region revealed that the region containing multiple nuclear receptor binding motifs located at -7.8 kilobases [termed nuclear receptor-responsive module (NURREM)], to which PXR and CAR also bind, is essential for the VDR-mediated ABCB1 transactivation. Further reporter assays with constructs containing truncated NURREM and gel shift assays suggested simultaneous binding of multiple VDR/retinoid X receptor alpha heterodimers to NURREM. Furthermore, knockdown of VDR expression in LS174T cells blocked the LCA- and the 1,25-VD3-induced transcription of ABCB1 reporter genes. In human hepatoma HepG2 cells, in contrast with LS174T cells, 1,25-VD3 activated the ABCB1 transcription only in the presence of ectopically expressed VDR. These results suggest that the NR1I subfamily members regulate the ABCB1 expression sharing the binding sites within NURREM and that the physiologically produced LCA and 1,25-VD3 may modulate the ABCB1 expression in human intestines, possibly associated with interindividual variations of ABCB1 expression.
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PMID:Involvement of Vitamin D receptor in the intestinal induction of human ABCB1. 1946 Sep 46