TY - JOUR
T1 - Regulation of VDR expression in rat and human intestine and liver - Consequences for CYP3A expression
AU - Khan, Ansar A.
AU - Dragt, Bieuwke S.
AU - Porte, Robert J.
AU - Groothuis, Geny M.M.
PY - 2010/4
Y1 - 2010/4
N2 - The vitamin D receptor (VDR) regulates the expression of drug metabolizing enzymes and transporters in intestine and liver, but the regulation of VDR expression in intestine and liver is incompletely understood. We studied the regulation of VDR mRNA expression by ligands for VDR, farnesoid X receptor (FXR), glucocorticoid receptor (GR) and protein kinase C α (PKCα) in rat and human ileum and liver using precision-cut slices. 1,25(OH)2D3 induced VDR expression in rat ileum and liver, and human ileum but not in liver. Chenodeoxycholic acid (CDCA), but not lithocholic acid (LCA) and GW4064 induced VDR mRNA expression in rat ileum and liver. The PKCα activator, phorbol-12-myristate-13-acetate (PMA) induced the expression of VDR in the rat liver, and the induction of VDR by 1,25(OH)2D3 and CDCA was inhibited by the PKCα inhibitor, bisindolyl maleimide I (Bis I). These results show that the expression of VDR is likely to be regulated by PKC but not by FXR or VDR activation at least in the rat liver. The VDR mediated induction of its target genes CYP3A1 and CYP3A2 by 1,25(OH)2D3 or LCA in the rat ileum was strongly reduced in the presence of CDCA despite the higher VDR expression. Thus, CDCA might potentiate the toxicity of LCA by inhibiting its metabolism.
AB - The vitamin D receptor (VDR) regulates the expression of drug metabolizing enzymes and transporters in intestine and liver, but the regulation of VDR expression in intestine and liver is incompletely understood. We studied the regulation of VDR mRNA expression by ligands for VDR, farnesoid X receptor (FXR), glucocorticoid receptor (GR) and protein kinase C α (PKCα) in rat and human ileum and liver using precision-cut slices. 1,25(OH)2D3 induced VDR expression in rat ileum and liver, and human ileum but not in liver. Chenodeoxycholic acid (CDCA), but not lithocholic acid (LCA) and GW4064 induced VDR mRNA expression in rat ileum and liver. The PKCα activator, phorbol-12-myristate-13-acetate (PMA) induced the expression of VDR in the rat liver, and the induction of VDR by 1,25(OH)2D3 and CDCA was inhibited by the PKCα inhibitor, bisindolyl maleimide I (Bis I). These results show that the expression of VDR is likely to be regulated by PKC but not by FXR or VDR activation at least in the rat liver. The VDR mediated induction of its target genes CYP3A1 and CYP3A2 by 1,25(OH)2D3 or LCA in the rat ileum was strongly reduced in the presence of CDCA despite the higher VDR expression. Thus, CDCA might potentiate the toxicity of LCA by inhibiting its metabolism.
UR - http://www.scopus.com/inward/record.url?scp=77649336223&partnerID=8YFLogxK
U2 - 10.1016/j.tiv.2009.12.011
DO - 10.1016/j.tiv.2009.12.011
M3 - Article
C2 - 20006981
AN - SCOPUS:77649336223
SN - 0887-2333
VL - 24
SP - 822
EP - 829
JO - Toxicology in Vitro
JF - Toxicology in Vitro
IS - 3
ER -