Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR

Abstract

Zhang J, Huang W, Chua SS, et al (Baylor College of Medicine, Houston, TX) Overdoses of acetaminophen are the leading cause of hospital admission for acute liver failure in the United States. Ingestion of only 2 to 3 times the maximum daily recommended dose of acetaminophen can cause hepatotoxicity, and higher doses result in potentially fatal centrilobular necrosis. Acetaminophen toxicity is increased in both human beings and rodents by pretreatment with various inducers of CYP gene expression, including ethanol and phenobarbital. Because the xenobiotic receptor CAR has recently been shown to mediate the effects of phenobarbital and other phenobarbital-like inducers, the effects of phenobarbital and the potent CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) on acetaminophen toxicity were examined in wild-type and CAR knockout mice. Both strains of mice were treated with inducers or the vehicle control, followed by acetaminophen (250 mg/kg of body weight). The known CAR activators and the high dose of acetaminophen induced expression of 3 acetaminophen-metabolizing enzymes in wild-type mice but not in the CAR null mice. The CAR null mice were resistant to acetaminophen toxicity. Inhibition of CAR activity by administration by the inverse agonist ligand androstanol 1 hour after acetaminophen treatment blocked hepatotoxicity in wild-type but not in CAR null mice. These findings demonstrate that CAR is a central mediator of acetaminophen toxicity in mice and potentially also in human beings. It would appear that CAR is not involved in the toxicity associated with ethanol-dependent induction of CYP2E1 and other targets because CAR activation caused a modest decrease in CYP2E1 mRNA levels. However, activation of either mouse or human CAR by appropriate inducers, including acetaminophen itself, increased the production of APAP-metabolizing enzymes and increased toxicity. Fatal outcomes have been reported to result from the combination of phenobarbital and acetaminophen in human beings. The findings of this study suggest a new strategy for treatment of acetaminophen toxicity based on the use of CAR agonists.