Constitutive Androstane Receptor

DeKeyser, Joshua G.; Omiecinski, Curtis J.

doi:10.1016/b978-0-08-046884-6.00211-6

Cited by 4 publications

(6 citation statements)

References 133 publications

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“…A large number of pharmaceutical compounds, natural product constituents, and other xenobiotic chemicals have been identified as CAR activators (Chang and Waxman, 2006), establishing the importance of this receptor pathway as a key modulator of xenobiotic-induced toxicity and as an important mediator of physiological processes including lipid homeostasis and bile acid elimination (Dekeyser and Omiecinski, 2010). CAR is unusual among nuclear receptors in that it possesses high constitutive activity in the absence of ligand.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

“…The constitutive androstane receptor (CAR; NR1I3) is a member of the nuclear hormone receptor superfamily and expressed primarily in the liver (Dekeyser and Omiecinski, 2010). Along with PXR (NR1I2), CAR functions as a xenosensor and transcriptional regulator of genes encoding all three phases of drug metabolism (Dekeyser and Omiecinski, 2010;Pascussi et al, 2008). A wide range of exogenous substances have been identified that activate these receptors, events that often result in altered pharmacokinetic profiles for many clinically important medications as well as in modified rates of either detoxication or bioactivation of environmental chemicals (Dekeyser and Omiecinski, 2010;Pascussi et al, 2008).…”

mentioning

confidence: 99%

“…Along with PXR (NR1I2), CAR functions as a xenosensor and transcriptional regulator of genes encoding all three phases of drug metabolism (Dekeyser and Omiecinski, 2010;Pascussi et al, 2008). A wide range of exogenous substances have been identified that activate these receptors, events that often result in altered pharmacokinetic profiles for many clinically important medications as well as in modified rates of either detoxication or bioactivation of environmental chemicals (Dekeyser and Omiecinski, 2010;Pascussi et al, 2008). In addition, both CAR and PXR have been established as key physiological regulators, affecting processes such as lipid homeostasis, glucose and energy metabolism, and bile acid elimination (Echchgadda et al, 2007;Gao and Xie, 2010;Maglich et al, 2004;Maglich et al, 2009).…”

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confidence: 99%

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Multi-species Analyses of Direct Activators of the Constitutive Androstane Receptor

Omiecinski

Coslo

Chen

et al. 2011

Toxicological Sciences

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The constitutive androstane receptor (CAR; NR1I3) is a member of the nuclear receptor superfamily and functions as an important xenochemical sensor and transcriptional modulator in mammalian cells. Upon chemical activation, CAR undergoes nuclear translocation and heterodimerization with the retinoid X receptor subsequent to its DNA target interaction. CAR is unusual among nuclear receptors in that it possesses a high level of constitutive activity in cell-based assays, obscuring the detection of ligand activators. However, a human splice variant of CAR, termed CAR3, exhibits negligible constitutive activity. In addition, CAR3 is activated by ligands with similar specificity as the reference form of the receptor. In this study, we hypothesized that similar CAR3 receptors could be constructed across various mammalian species' forms of CAR that would preserve species-specific ligand responses, thus enabling a more sensitive and differential screening assessment of CAR response among animal models. A battery of CAR3 receptors was produced in mouse, rat, and dog and comparatively evaluated with selected ligands together with human CAR1 and CAR3 in mammalian cell reporter assays. The results demonstrate that the 5-amino acid insertion that typifies human CAR3 also imparts ligand-activated receptor function in other species' CAR while maintaining signature responses in each species to select CAR ligands. These variant constructs permit in vitro evaluation of differential chemical effector responses across species and coupled with in vivo assays, the species-selective contributions of CAR in normal physiology and in disease processes such as hepatocarcinogenesis.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Multi-species Analyses of Direct Activators of the Constitutive Androstane Receptor

Omiecinski

Coslo

Chen

et al. 2011

Toxicological Sciences

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“…And the nuclear receptor CAR (Constitutive Androstane Receptor) is mainly expressed in liver, where it is activated by structurally diverse ligands and then regulates cytochrome P450 and other genes whose products are involved in DMEs and transporters (Tien and Negishi, 2006;Osabe et al, 2009;DeKeyser and Omiecinsk, 2010). Therefore, CAR plays central role in protecting the body against xenobiotics and endogenous substances (Honkakoski and Negishi, 2000;Maglich et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Identification of the Pig Constitutive Androstane Receptor (pgCAR) Agonist using a High-throughput Screening Assay

Lou¹,

Wang²,

Shi³

et al. 2017

IJAB

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Pigs are encountering a large number of xenobiotics potentially harmful consequences, which is not only bad for animal health and pork quality but also bad for human health. Therefore, identification of the Pig Constitutive Androstane Receptor (pgCAR) agonist would be beneficial for pigs and consumer, because of its pivotal role in xenobiotics-metabolism. In this study, A stable and sensitive cell-based high throughput screening (HTS) model is conducted in a 48-well format using the human hepatoma HepG2 cells transiently transfected with pcDNA3.1-pgCAR plasmid and reporter plasmids to identify chemicals or natural compounds that would promote CAR，and calibrated with reference pgCAR agonist, phenytoin. In conclusion, three active ingredients including Vitamin C, Folate and Sitosterol, were picked out as agonists by the high-throughput screening from 13 compounds, particularly the effects of Sitosterol.

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Effects of rifampicin on hepatic antioxidant enzymes in PXR and CAR double humanized mice

Choi

Ryu

Lee

et al. 2021

Mol. Cell. Toxicol.

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Constitutive Androstane Receptor

Cited by 4 publications

References 133 publications

Multi-species Analyses of Direct Activators of the Constitutive Androstane Receptor

Multi-species Analyses of Direct Activators of the Constitutive Androstane Receptor

Identification of the Pig Constitutive Androstane Receptor (pgCAR) Agonist using a High-throughput Screening Assay

Effects of rifampicin on hepatic antioxidant enzymes in PXR and CAR double humanized mice

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