Involvement of Vitamin D Receptor in the Intestinal Induction of Human ABCB1

1α,25-Dihydroxyvitamin D3Up-Regulates P-Glycoprotein via the Vitamin D Receptor and Not Farnesoid X Receptor in Bothfxr(−/−) andfxr(+/+) Mice and Increased Renal and Brain Efflux of Digoxin in Mice In Vivo

“…Unequivocally, the induction of Mdr1/P-gp in the rat and mouse by the VDR has been translated to observations in human cell lines, and the intestinal P-gp may be further involved in DDIs. VDR activation of MDR1 mRNA and P-gp had been observed in human colonic cell lines (Aiba et al, 2005;Fan et al, 2009;Tachibana et al, 2009), a notion consistent with the existence of vitamin D response elements (Saeki et al, 2008). As a result, it is highly likely that 1,25(OH) 2 D 3 treatment in combination with other therapeutic agents would cause significant DDIs.…”

“…The vitamin D receptor (VDR) displays similar homology with PXR and constitutive androstane receptor (Reschly and Krasowski, 2006) and is another nuclear receptor that transactivates MDR1. 1␣, [1,25(OH) 2 D 3 ], the natural, active ligand of VDR (Tanaka et al, 1973), resulted in up-regulation of MDR1/P-gp expression in human colon carcinoma cell lines such as Caco-2, LS180, and LS174T cells (Aiba et al, 2005;Fan et al, 2009;Tachibana et al, 2009) and elevated P-gp levels in human airway epithelium-derived Caclu-3 cells (Patel et al, 2002). These results are consistent with the existence of a vitamin D response element in the MDR1 gene (Saeki et al, 2008).…”

The SLCO1A2 Gene, Encoding Human Organic Anion-Transporting Polypeptide 1A2, Is Transactivated by the Vitamin D Receptor

“…Another study showed that mRNA levels for multidrug resistance protein 1 (ABCB1) and multidrug resistance-associated protein (MRP) 2 (ABCC2), as well as protein levels for MRP4 (ABCC4), were significantly increased with vitamin D 3 treatment of Caco-2 cells, whereas expression of the apical sodium- dependent bile acid transporter (SLC10A2), oligopeptide transporter 1 (SLC15A1), and MRP3 (ABCC3) were not affected (Fan et al, 2009). Tachibana et al (2009) verified that the induction of multidrug resistance protein 1 expression is VDR-dependent. Given that human ABCB1 gene expression is also induced by the other two nuclear receptors, PXR (NRI12) and constitutive androstane receptor (NRI13) (Geick et al, 2001;Burk et al, 2005), the three members of the NRI1 nuclear receptor subfamily seem to carry out overlapping functions in intestinal drug transport.…”

“…It was reported that a number of genes encoding intestinal membrane transporters for both endogenous substances and drugs and xenobiotics are regulated by vitamin D 3 and VDR Fan et al, 2009;Tachibana et al, 2009;Chow et al, 2010;Maeng et al, 2011). We have investigated whether vitamin D 3 and VDR regulate the expression of the SLCO1A2 gene, which encodes an important membrane transporter for intestinal absorption of numerous drugs.…”

Effects of 1α,25-Dihydroxyvitamin D₃ on Intestinal Absorption and Disposition of Adefovir Dipivoxil and Its Metabolite, Adefovir, in Rats

“…1,25(OH) 2 D 3 increases the mRNA expression and function of multidrug resistance protein 1 (MDR1) in the human colorectal adenocarcinoma cell lines, LS174T and Caco-2 cells in vitro. 8,12) It also increases the protein expressions of multidrug resistance-associated protein 2 and 4 (MRP2 and MRP4) in Caco-2 cells. 8,13) In rats, 1,25(OH) 2 D 3 treatment in vivo increases the protein expressions of Mrp2, Mrp3, Mrp4, and the oligopeptide transporter 1 (PepT1) without altering the mRNA and protein expressions of Mdr1a (P-glycoprotein; P-gp).…”