Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A double null mouse line (2XENKO) lacking the xenobiotic receptors CAR (constitutive androstane receptor) (NR1I3) and PXR (pregnane X receptor) (NR1I2) was generated to study their functions in response to potentially toxic xenobiotic and endobiotic stimuli. Like the single knockouts, the 2XENKO mice are viable and fertile and show no overt phenotypes under normal conditions. As expected, they are completely insensitive to broad range xenobiotic inducers able to activate both receptors, such as clotrimazole and dieldrin. Comparisons of the single and double knockouts reveal specific roles for the two receptors. Thus, PXR does not contribute to the process of acetaminophen hepatotoxicity mediated by CAR, but both receptors contribute to the protective response to the hydrophobic bile acid lithocholic acid (LCA). As previously observed with PXR (Xie, W., Radominska-Pandya, A., Shi, Y., Simon, C. M., Nelson, M. C., Ong, E. S., Waxman, D. J., and Evans, R. M. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 3375-3380), pharmacologic activation of CAR induces multiple LCA detoxifying enzymes and provides strong protection against LCA toxicity. Comparison of their responses to LCA treatment demonstrates that CAR predominantly mediates induction of the cytochrome p450 CYP3A11 and the multidrug resistance-associated protein 3 transporter, whereas PXR is the major regulator of the Na+-dependent organic anion transporter 2. These differential responses may account for the significant sensitivity of the CAR knockouts, but not the PXR knockouts, to an acute LCA dose. Because this sensitivity is not further increased in the 2XENKO mice, CAR may play a primary role in acute responses to this toxic endobiotic. These results define a central role for CAR in LCA detoxification and show that CAR and PXR function coordinately to regulate both xenobiotic and bile acid metabolism.
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PMID:The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity. 1535 66

Chemicals that increase expression of phase-I and -II biotransformation enzymes in liver, as well as enhance hepatic uptake and biliary excretion are often referred to as microsomal enzyme inducers (MEIs). Early studies suggested that drug metabolism might be coordinately regulated along with drug efflux from hepatocytes as a means for the liver to rid itself of foreign chemicals. Since then, the identification and characterization of nuclear receptors (NRs) has aided in understanding of how various MEIs enhance xeniobiotic uptake, biotransformation, and excretion. In addition, the NRs by which several classes of MEIs induce phase-I and -II drug metabolizing enzymes have been elucidated (i.e. AHR, CAR, PXR, PPARalpha, Nrf2). Several transporter families which mediate uptake of chemicals into liver and excretion of chemicals from liver into blood and/or bile have been cloned and identified. In general, the organic anion transporting polypeptide family (Oatps) along with Organic cation transporter 1 (Oct1) and Organic anion transporter 2 mediate uptake of a large number of xenobiotics from blood into liver. Conversely, Multidrug resistance proteins (Mdrs), Multidrug resistance-associated proteins (Mrps), and Breast cancer resistance protein (Bcrp) mediate efflux of xenobiotics from liver into bile or blood. Recent studies have demonstrated that MEIs increase expression of various Oatps, Mrps, and Mdrs in liver, and some occur via activation of nuclear receptors.
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PMID:Regulation of hepatic transporters by xenobiotic receptors. 1610 71