Alterations in xenobiotic metabolism in the long-lived Little mice.

Alterations in xenobiotic metabolism in the long-lived Little mice. Research Abstract Details 

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Alterations in xenobiotic metabolism in the long-lived Little mice. Abstract Text:

Our previous microarray expression analysis of the long-lived Little mice (Ghrhr(lit/lit)) showed a concerted up-regulation of xenobiotic detoxification genes. Here, we show that this up-regulation is associated with a potent increase in resistance against the adverse effects of a variety of xenobiotics, including the hepatotoxins acetaminophen and bromobenzene and the paralyzing agent zoxazolamine. The classic xenobiotic receptors Car (Constitutive Androstane Receptor) and Pxr (Pregnane X Receptor) are considered key regulators of xenobiotic metabolism. Using double and triple knockout/mutant mouse models we found, however, that Car and Pxr are not required for the up-regulation of xenobiotic genes in Little mice. Our results suggest instead that bile acids and the primary bile acid receptor Fxr (farnesoid X receptor) are likely mediators of the up-regulation of xenobiotic detoxification genes in Little mice. Bile acid levels are considerably elevated in the bile, serum, and liver of Little mice. We found that treatment of wild-type animals with cholic acid, one of the major bile acids elevated in Little mice, mimics in large part the up-regulation of xenobiotic detoxification genes observed in Little mice. Additionally, the loss of Fxr had a major effect on the expression of the xenobiotic detoxification genes up-regulated in Little mice. A large fraction of these genes lost or decreased their high expression levels in double mutant mice for Fxr and Ghrhr. The alterations in xenobiotic metabolism in Little mice constitute a form of increased stress resistance and may contribute to the extended longevity of these mice.

Alterations in xenobiotic metabolism in the long-lived Little mice. Publishing Authors By Initials

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Alterations in xenobiotic metabolism in the long-lived Little mice. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Aging cell

VOLUME: 6

Page Numbers: 453-70

Journal Abbreviation: Aging Cell

ISSN: 1474-9718

DAY: 23

MONTH: 05

YEAR: 2007

Alterations in xenobiotic metabolism in the long-lived Little mice. Information

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LANGUAGE: eng

NlmUniqueID: 101130839

Alterations in xenobiotic metabolism in the long-lived Little mice. Keywords Mesh Terms:

KEYWORDS: Xenobiotics

MESH TERMS: toxicity

Chemical & Substance for Abstract: Alterations in xenobiotic metabolism in the long-lived Little mice. Information

Substance Name: pregnane X receptor

Registry Number: 0

Grant and Affiliation Information for Alterations in xenobiotic metabolism in the long-lived Little mice.

AFFILIATION: Molecular & Human Genetics Department, Baylor College of Medicine, Houston, TX 77030, USA. da135453@bcm.tmc.edu

Country: England

AGENCY: United States NIDDK

GRANT: DK56338

ACRONYM: DK

MEDLINETA: Aging Cell

REFSOURCE: Aging Cell. 2007 Aug;6(4):421-3

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