In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice. / Scheer, Nico; Ross, Jillian; Kapelyukh, Yury; Rode, Anja; Wolf, C. Roland.
In: Drug Metabolism and Disposition, Vol. 38, No. 7, 07.2010, p. 1046-1053.Research output: Contribution to journal › Article
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TY - JOUR
T1 - In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice
A1 - Scheer,Nico
A1 - Ross,Jillian
A1 - Kapelyukh,Yury
A1 - Rode,Anja
A1 - Wolf,C. Roland
AU - Scheer,Nico
AU - Ross,Jillian
AU - Kapelyukh,Yury
AU - Rode,Anja
AU - Wolf,C. Roland
PY - 2010/7
Y1 - 2010/7
N2 - <p>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.</p>
AB - <p>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.</p>
KW - CONSTITUTIVE ANDROSTANE RECEPTOR
KW - ACETAMINOPHEN-INDUCED HEPATOTOXICITY
KW - HUMAN HEPATOCYTES
KW - NUCLEAR RECEPTORS
KW - HUMAN-LIVER
KW - GLUCOCORTICOID-RECEPTOR
KW - XENOBIOTIC RESPONSE
KW - DRUG-METABOLISM
KW - GENE-EXPRESSION
KW - MOUSE MODELS
U2 - 10.1124/dmd.109.031872
DO - 10.1124/dmd.109.031872
M1 - Article
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
SN - 0090-9556
IS - 7
VL - 38
SP - 1046
EP - 1053
ER -