Comparison of effects of VDR versus PXR, FXR and GR ligands on the regulation of CYP3A isozymes in rat and human intestine and liver.
In this study, we compared the regulation of CYP3A isozymes by the vitamin D receptor (VDR) ligand 1 alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) against ligands of the pregnane X receptor (PXR), the glucocorticoid receptor (GR) and the farnesoid X receptor (FXR) in precision-cut tissue slices of the rat jejunum, ileum, colon and liver, and human ileum and liver. In the rat, 1,25(OH)(2)D(3) strongly induced CYP3A1 mRNA, quantified by qRT-PCR, along the entire length of the intestine, induced CYP3A2 only in ileum but had no effect on CYP3A9. In contrast, the PXR/GR ligand, dexamethasone (DEX), the PXR ligand, pregnenolone-16 alpha carbonitrile (PCN), and the FXR ligand, chenodeoxycholic acid (CDCA), but not the GR ligand, budesonide (BUD), induced CYP3A1 only in the ileum, none of them influenced CYP3A2 expression, and PCN, DEX and BUD but not CDCA induced CYP3A9 in jejunum, ileum and colon. In rat liver, CYP3A1, CYP3A2 and CYP3A9 mRNA expression was unaffected by 1,25(OH)(2)D(3), whereas CDCA decreased the mRNA of all CYP3A isozymes; PCN induced CYP3A1 and CYP3A9, BUD induced CYP3A9, and DEX induced all three CYP3A isozymes. In human ileum and liver, 1,25(OH)(2)D(3) and DEX induced CYP3A4 expression, whereas CDCA induced CYP3A4 expression in liver only. In conclusion, the regulation of rat CYP3A isozymes by VDR, PXR, FXR and GR ligands differed for different segments of the rat and human intestine and liver, and the changes did not parallel expression levels of the nuclear receptors.
Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, Ant. Deusinglaan 1, 9713 AV, Groningen, The Netherlands. a.a.khan@rug.nl
Ansar A
AA
Khan
Edwin C Y
EC
Chow
Anne-miek M A
AM
van Loenen-Weemaes
Robert J
RJ
Porte
K Sandy
KS
Pang
Geny M M
GM
Groothuis
D000818:Animals; D001483:Base Sequence; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D006801:Humans; D066298:In Vitro Techniques; D007422:Intestines / Q000201:enzymology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000201:enzymology*; D008297:Male; D016133:Polymerase Chain Reaction; D000077297:Pregnane X Receptor; D051381:Rats; D017208:Rats, Wistar; D018167:Receptors, Calcitriol / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D051544:Cytochrome P-450 CYP3A; D017931:DNA Primers; D007527:Isoenzymes; D008024:Ligands; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D000099150:Receptor, Farnesoid X-Activated