Discovery - University of Dundee - Online Publications

Library & Learning Centre

In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice

In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice

Research output: Contribution to journalArticle

View graph of relations

Authors

Research units

    Info

    Original languageEnglish
    Pages1046-1053
    Number of pages8
    JournalDrug Metabolism and Disposition
    Journal publication dateJul 2010
    Journal number7
    Volume38
    DOIs
    StatePublished

    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.

    Documents

    Library & Learning Centre

    Contact | Accessibility | Policy