The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity.
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.
Zhang
Jun
J
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Huang
Wendong
W
Qatanani
Mohammed
M
Evans
Ronald M
RM
Moore
David D
DD
D000082:Acetaminophen / Q000494:pharmacology; D000410:Alanine Transaminase / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism*; D001663:Bilirubin / Q000378:metabolism; D015152:Blotting, Northern; D003022:Clotrimazole / Q000494:pharmacology; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D003902:Detergents / Q000494:pharmacology; D004026:Dieldrin / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D008095:Lithocholic Acid / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010641:Phenotype; D000077297:Pregnane X Receptor; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D011987:Receptors, Steroid / Q000378:metabolism / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
D018712:Analgesics, Non-Narcotic; D001647:Bile Acids and Salts; D000090702:Constitutive Androstane Receptor; D003902:Detergents; D006131:Growth Inhibitors; D008565:Membrane Proteins; C000625853:Nr1i2 protein, mouse; C000716328:Nr1i3 protein, mouse; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D000082:Acetaminophen; D008095:Lithocholic Acid; D012313:RNA; D012964:Sodium; D001189:Aryl Hydrocarbon Hydroxylases; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000410:Alanine Transaminase; D003022:Clotrimazole; D004026:Dieldrin; D001663:Bilirubin