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

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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 journalArticle

Harvard

Scheer, N, Ross, J, Kapelyukh, Y, Rode, A & Wolf, CR 2010, 'In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice' Drug Metabolism and Disposition, vol 38, no. 7, pp. 1046-1053., 10.1124/dmd.109.031872

APA

Scheer, N., Ross, J., Kapelyukh, Y., Rode, A., & Wolf, C. R. (2010). In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice. Drug Metabolism and Disposition, 38(7), 1046-1053. 10.1124/dmd.109.031872

Vancouver

Scheer N, Ross J, Kapelyukh Y, Rode A, Wolf CR. In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice. Drug Metabolism and Disposition. 2010 Jul;38(7):1046-1053. Available from: 10.1124/dmd.109.031872

Author

Scheer, Nico; Ross, Jillian; Kapelyukh, Yury; Rode, Anja; Wolf, C. Roland / In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice.

In: Drug Metabolism and Disposition, Vol. 38, No. 7, 07.2010, p. 1046-1053.

Research output: Contribution to journalArticle

Bibtex - Download

@article{51eab7f545d54bc79c3cb7c0355c16c4,
title = "In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice",
keywords = "CONSTITUTIVE ANDROSTANE RECEPTOR, ACETAMINOPHEN-INDUCED HEPATOTOXICITY, HUMAN HEPATOCYTES, NUCLEAR RECEPTORS, HUMAN-LIVER, GLUCOCORTICOID-RECEPTOR, XENOBIOTIC RESPONSE, DRUG-METABOLISM, GENE-EXPRESSION, MOUSE MODELS",
author = "Nico Scheer and Jillian Ross and Yury Kapelyukh and Anja Rode and Wolf, {C. Roland}",
year = "2010",
doi = "10.1124/dmd.109.031872",
volume = "38",
number = "7",
pages = "1046--1053",
journal = "Drug Metabolism and Disposition",
issn = "0090-9556",

}

RIS (suitable for import to EndNote) - Download

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 -

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