Regulation of VDR expression in rat and human intestine and liver--consequences for CYP3A expression.
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 alpha (PKCalpha) in rat and human ileum and liver using precision-cut slices. 1,25(OH)(2)D(3) 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 PKCalpha 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)(2)D(3) and CDCA was inhibited by the PKCalpha 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)(2)D(3) 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.
Khan
Ansar A
AA
Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, Ant Deusinglaan 1, 9713 AV Groningen, The Netherlands. a.a.khan@rug.nl
Dragt
Bieuwke S
BS
Porte
Robert J
RJ
Groothuis
Geny M M
GM
D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000201:enzymology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008095:Lithocholic Acid / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008301:Maleimides / Q000494:pharmacology; D051571:Protein Kinase C-alpha / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018167:Receptors, Calcitriol / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D000099150:Receptor, Farnesoid X-Activated
D051544:Cytochrome P-450 CYP3A; D007211:Indoles; D008095:Lithocholic Acid; D008301:Maleimides; D051571:Protein Kinase C-alpha; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D013755:Tetradecanoylphorbol Acetate; D000099150:Receptor, Farnesoid X-Activated; C088060:bisindolylmaleimide