Submitted to: Science
Publication Type: Peer reviewed journal
Publication Acceptance Date: 8/16/2002
Publication Date: 10/11/2002
Citation: Zhang, J., Huang, W., Chua, S.S., Wei, P., Moore, D.D. 2002. Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science. 298(5592):422-424. Interpretive Summary: Overdoses of acetaminophen cause severe damage to the liver. This study showed that high levels of acetaminophen activate the nuclear receptor CAR, which increases the rate of conversion of acetaminophen to a toxic product. Blocking CAR activity protects against the harmful effects of acetaminophen. These results suggest an innovative therapeutic approach for treating the adverse effects of acetaminophen and potentially other hepatotoxic agents.
Technical Abstract: 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.