In vivo responses of the human and murine pregnane X receptor to dexamethasone in mice.
Dexamethasone (DEX) is a potent and widely used anti-inflammatory and immunosuppressant glucocorticoid. It can bind and activate the pregnane X receptor (PXR), which plays a critical role as xenobiotic sensor in mammals to induce the expression of many enzymes, including cytochromes P450 in the CYP3A family. This induction results in its own metabolism. We have used a series of transgenic mouse lines, including a novel, improved humanized PXR line, to compare the induction profile of PXR-regulated drug-metabolizing enzymes after DEX administration, as well as looking at hepatic responses to rifampicin (RIF). The new humanized PXR model has uncovered further intriguing differences between the human and mouse receptors in that RIF only induced Cyp2b10 in the new humanized model. DEX was found to be a much more potent inducer of Cyp3a proteins in wild-type mice than in mice humanized for PXR. To assess whether PXR is involved in the detoxification of DEX in the liver, we analyzed the consequences of high doses of the glucocorticoid on hepatotoxicity on different PXR genetic backgrounds. We also studied these effects in an additional mouse model in which functional mouse Cyp3a genes have been deleted. These strains exhibited different sensitivities to DEX, indicating a protective role of the PXR and CYP3A proteins against the hepatotoxicity of this compound.
Scheer
Nico
N
TaconicArtemis, Cologne, Germany. nico.scheer@taconicartemis.com
Ross
Jillian
J
Kapelyukh
Yury
Y
Rode
Anja
A
Wolf
C Roland
CR
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D002461:Cell Line, Transformed; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D003907:Dexamethasone / Q000493:pharmacokinetics / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000096:biosynthesis* / Q000187:drug effects*; D012293:Rifampin / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins
D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D000072467:Cytochrome P450 Family 2; D003907:Dexamethasone; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D012293:Rifampin; D013250:Steroid Hydroxylases; C101679:Cyp2b10 protein, mouse; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins