Abstract
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.
Footnotes
This work was supported by ITI Life Sciences, Scotland.
Conflict of interest: N.S. and A.R. receive income from TaconicArtemis, and J.R., Y.K., and C.R.W. receive income from CXR Biosciences. The authors have declared that no conflict of interest exists.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.031872.
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ABBREVIATIONS:
- DEX
- dexamethasone
- P450
- cytochrome P450
- GR
- glucocorticoid receptor
- PXR
- pregnane X receptor
- CAR
- constitutive androstane receptor
- ET-743
- ecteinascidin 743
- huPXR
- humanized pregnane X receptor mice
- PCR
- polymerase chain reaction
- ES cell
- embryonic stem cell
- FLPe
- efficient FLP
- PXR KO
- pregnane X receptor knockout mice
- huPXRi
- improved humanized pregnane X receptor mice
- WT
- wild-type
- RIF
- rifampicin
- qRT
- quantitative reverse transcriptase
- hPXR
- human pregnane X receptor
- PAGE
- polyacrylamide gel electrophoresis
- PROD
- pentoxyresorufin dealkylation
- BQ
- 7-benzyloxyquinoline
- ALT
- alanine aminotransferase
- AUC
- area under the concentration versus time curve
- SET
- sucrose/EDTA/Tris-HCl.
- Received December 18, 2009.
- Accepted March 30, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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