Involvement of vitamin D receptor in the intestinal induction of human ABCB1

Shuko Tachibana, Kouichi Yoshinari, Tsubasa Chikada, Takayoshi Toriyabe, Kiyoshi Nagata, Yasushi Yamazoe

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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 1α,25-dihydroxyvitamin D3 (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 α 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.

Original languageEnglish
Pages (from-to)1604-1610
Number of pages7
JournalDrug Metabolism and Disposition
Volume37
Issue number8
DOIs
Publication statusPublished - 2009 Aug

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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    Tachibana, S., Yoshinari, K., Chikada, T., Toriyabe, T., Nagata, K., & Yamazoe, Y. (2009). Involvement of vitamin D receptor in the intestinal induction of human ABCB1. Drug Metabolism and Disposition, 37(8), 1604-1610. https://doi.org/10.1124/dmd.109.027219