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Science 298 (5592): 422-424

Copyright © 2002 by the American Association for the Advancement of Science

Modulation of Acetaminophen-Induced Hepatotoxicity by the Xenobiotic Receptor CAR

Jun Zhang,* Wendong Huang,* Steven S. Chua, Ping Wei,dagger David D. Mooreddagger

We have identified the xenobiotic receptor CAR (constitutive androstane receptor) as a key regulator of acetaminophen metabolism and hepatotoxicity. Known CAR activators as well as high doses of acetaminophen induced expression of three acetaminophen-metabolizing enzymes in wild-type but not in CAR null mice, and the CAR null mice were resistant to acetaminophen toxicity. Inhibition of CAR activity by administration of the inverse agonist ligand androstanol 1 hour after acetaminophen treatment blocked hepatotoxicity in wild type but not in CAR null mice. These results suggest an innovative therapeutic approach for treating the adverse effects of acetaminophen and potentially other hepatotoxic agents.

Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
*   These authors contributed equally to this work.

dagger    Present address: X-Ceptor Therapeutics Inc., 4757 Nexus Centre Drive, San Diego, CA 92121, USA.

ddagger    To whom correspondence should be addressed. E-mail: moore{at}bcm.tmc.edu



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