Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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}

Role of Constitutive Androstane Receptor in Toll-Like Receptor-Mediated Regulation of Gene Expression of Hepatic Drug-Metabolizing Enzymes and Transporters.
P. Shah, T. Guo, D. D. Moore, and R. Ghose (2014)
Drug Metab. Dispos. 42, 172-181
   Abstract »    Full Text »    PDF »
Studies on the Role of Metabolic Activation in Tyrosine Kinase Inhibitor-Dependent Hepatotoxicity: Induction of CYP3A4 Enhances the Cytotoxicity of Lapatinib in HepaRG Cells.
K. D. Hardy, M. D. Wahlin, I. Papageorgiou, J. D. Unadkat, A. E. Rettie, and S. D. Nelson (2014)
Drug Metab. Dispos. 42, 162-171
   Abstract »    Full Text »    PDF »
Acetaminophen Modulates P-Glycoprotein Functional Expression at the Blood-Brain Barrier by a Constitutive Androstane Receptor-Dependent Mechanism.
L. M. Slosky, B. J. Thompson, L. Sanchez-Covarrubias, Y. Zhang, M.-L. Laracuente, T. W. Vanderah, P. T. Ronaldson, and T. P. Davis (2013)
Mol. Pharmacol. 84, 774-786
   Abstract »    Full Text »    PDF »
Expression of Human CAR Splicing Variants in BAC-Transgenic Mice.
Y.-K. J. Zhang, H. Lu, and C. D. Klaassen (2013)
Toxicol. Sci. 132, 142-150
   Abstract »    Full Text »    PDF »
Targeted Drug Delivery to Treat Pain and Cerebral Hypoxia.
P. T. Ronaldson and T. P. Davis (2013)
Pharmacol. Rev. 65, 291-314
   Abstract »    Full Text »    PDF »
Lentiviral-Mediated RNAi Knockdown Yields a Novel Mouse Model for Studying Cyp2b Function.
B. Damiri, E. Holle, X. Yu, and W. S. Baldwin (2012)
Toxicol. Sci. 125, 368-381
   Abstract »    Full Text »    PDF »
Genomic modeling of tumor onset and progression in a mouse model of aggressive human liver cancer.
C. Coulouarn, V. M. Factor, E. A. Conner, and S. S. Thorgeirsson (2011)
Carcinogenesis 32, 1434-1440
   Abstract »    Full Text »    PDF »
Quantitative Prediction of Human Pregnane X Receptor and Cytochrome P450 3A4 Mediated Drug-Drug Interaction in a Novel Multiple Humanized Mouse Line.
M. Hasegawa, Y. Kapelyukh, H. Tahara, J. Seibler, A. Rode, S. Krueger, D. N. Lee, C. R. Wolf, and N. Scheer (2011)
Mol. Pharmacol. 80, 518-528
   Abstract »    Full Text »    PDF »
Transgenic Animal Models in Toxicology: Historical Perspectives and Future Outlook.
D. R. Boverhof, M. P. Chamberlain, C. R. Elcombe, F. J. Gonzalez, R. H. Heflich, L. G. Hernandez, A. C. Jacobs, D. Jacobson-Kram, M. Luijten, A. Maggi, et al. (2011)
Toxicol. Sci. 121, 207-233
   Abstract »    Full Text »    PDF »
Xenobiotic Metabolism, Disposition, and Regulation by Receptors: From Biochemical Phenomenon to Predictors of Major Toxicities.
C. J. Omiecinski, J. P. Vanden Heuvel, G. H. Perdew, and J. M. Peters (2011)
Toxicol. Sci. 120, S49-S75
   Abstract »    Full Text »    PDF »
A Functional Cross-Talk between Liver X Receptor-{alpha} and Constitutive Androstane Receptor Links Lipogenesis and Xenobiotic Responses.
Y. Zhai, T. Wada, B. Zhang, S. Khadem, S. Ren, R. Kuruba, S. Li, and W. Xie (2010)
Mol. Pharmacol. 78, 666-674
   Abstract »    Full Text »    PDF »
In Vivo Responses of the Human and Murine Pregnane X Receptor to Dexamethasone in Mice.
N. Scheer, J. Ross, Y. Kapelyukh, A. Rode, and C. R. Wolf (2010)
Drug Metab. Dispos. 38, 1046-1053
   Abstract »    Full Text »    PDF »
Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease.
B. Dong, P. K. Saha, W. Huang, W. Chen, L. A. Abu-Elheiga, S. J. Wakil, R. D. Stevens, O. Ilkayeva, C. B. Newgard, L. Chan, et al. (2009)
PNAS 106, 18831-18836
   Abstract »    Full Text »    PDF »
Rifampicin-Activated Human Pregnane X Receptor and CYP3A4 Induction Enhance Acetaminophen-Induced Toxicity.
J. Cheng, X. Ma, K. W. Krausz, J. R. Idle, and F. J. Gonzalez (2009)
Drug Metab. Dispos. 37, 1611-1621
   Abstract »    Full Text »    PDF »
Di(2-ethylhexyl) phthalate Is a Highly Potent Agonist for the Human Constitutive Androstane Receptor Splice Variant CAR2.
J. G. DeKeyser, M. C. Stagliano, S. S. Auerbach, K. S. Prabhu, A. D. Jones, and C. J. Omiecinski (2009)
Mol. Pharmacol. 75, 1005-1013
   Abstract »    Full Text »    PDF »
Role of Enzymatic N-Hydroxylation and Reduction in Flutamide Metabolite-Induced Liver Toxicity.
M. Ohbuchi, M. Miyata, D. Nagai, M. Shimada, K. Yoshinari, and Y. Yamazoe (2009)
Drug Metab. Dispos. 37, 97-105
   Abstract »    Full Text »    PDF »
A Concentration Addition Model for the Activation of the Constitutive Androstane Receptor by Xenobiotic Mixtures.
W. S. Baldwin and J. A. Roling (2009)
Toxicol. Sci. 107, 93-105
   Abstract »    Full Text »    PDF »
The Peripheral Benzodiazepine Receptor Ligand 1-(2-Chlorophenyl-methylpropyl)-3-isoquinoline-carboxamide Is a Novel Antagonist of Human Constitutive Androstane Receptor.
L. Li, T. Chen, J. D. Stanton, T. Sueyoshi, M. Negishi, and H. Wang (2008)
Mol. Pharmacol. 74, 443-453
   Abstract »    Full Text »    PDF »
Human Hepatocytes Can Repopulate Mouse Liver: Histopathology of the Liver in Human Hepatocyte-Transplanted Chimeric Mice and Toxicologic Responses to Acetaminophen.
Y. Sato, H. Yamada, K. Iwasaki, C. Tateno, T. Yokoi, K. Yoshizato, and I. Horii (2008)
Toxicol Pathol 36, 581-591
   Abstract »    Full Text »    PDF »
Induction of Nuclear Translocation of Constitutive Androstane Receptor by Peroxisome Proliferator-activated Receptor {alpha} Synthetic Ligands in Mouse Liver.
D. Guo, J. Sarkar, K. Suino-Powell, Y. Xu, K. Matsumoto, Y. Jia, S. Yu, S. Khare, K. Haldar, M. S. Rao, et al. (2007)
J. Biol. Chem. 282, 36766-36776
   Abstract »    Full Text »    PDF »
The Environmental Estrogen, Nonylphenol, Activates the Constitutive Androstane Receptor.
J. P. Hernandez, W. Huang, L. M. Chapman, S. Chua, D. D. Moore, and W. S. Baldwin (2007)
Toxicol. Sci. 98, 416-426
   Abstract »    Full Text »    PDF »
Genomic Profiling in Nuclear Receptor-Mediated Toxicity.
C. G. Woods, J. P. Vanden Heuvel, and I. Rusyn (2007)
Toxicol Pathol 35, 474-494
   Abstract »    Full Text »    PDF »
CAR2 Displays Unique Ligand Binding and RXR{alpha} Heterodimerization Characteristics.
S. S. Auerbach, J. G. DeKeyser, M. A. Stoner, and C. J. Omiecinski (2007)
Drug Metab. Dispos. 35, 428-439
   Abstract »    Full Text »    PDF »
F. J. Gonzalez (2007)
Drug Metab. Dispos. 35, 1-8
   Abstract »    Full Text »    PDF »
International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor {alpha}, Farnesoid X Receptor beta, Liver X Receptor {alpha}, Liver X Receptor beta, and Vitamin D Receptor.
D. D. Moore, S. Kato, W. Xie, D. J. Mangelsdorf, D. R. Schmidt, R. Xiao, and S. A. Kliewer (2006)
Pharmacol. Rev. 58, 742-759
   Abstract »    Full Text »    PDF »
Dietary Inulin Alleviates Hepatic Steatosis and Xenobiotics-Induced Liver Injury in Rats Fed a High-Fat and High-Sucrose Diet: Association with the Suppression of Hepatic Cytochrome P450 and Hepatocyte Nuclear Factor 4{alpha} Expression.
J. Sugatani, T. Wada, M. Osabe, K. Yamakawa, K. Yoshinari, and M. Miwa (2006)
Drug Metab. Dispos. 34, 1677-1687
   Abstract »    Full Text »    PDF »
Functional Inhibitory Cross-talk between Constitutive Androstane Receptor and Hepatic Nuclear Factor-4 in Hepatic Lipid/Glucose Metabolism Is Mediated by Competition for Binding to the DR1 Motif and to the Common Coactivators, GRIP-1 and PGC-1{alpha}.
J. Miao, S. Fang, Y. Bae, and J. K. Kemper (2006)
J. Biol. Chem. 281, 14537-14546
   Abstract »    Full Text »    PDF »
In vivo role of the HNF4{alpha} AF-1 activation domain revealed by exon swapping.
N. Briancon and M. C. Weiss (2006)
EMBO J. 25, 1253-1262
   Abstract »    Full Text »    PDF »
K. K. Wolf, S. G. Wood, J. A. Hunt, B. W. Walton-Strong, K. Yasuda, L. Lan, S. X. Duan, Q. Hao, S. A. Wrighton, E. H. Jeffery, et al. (2005)
Drug Metab. Dispos. 33, 1827-1836
   Abstract »    Full Text »    PDF »
Retinoid X Receptor {alpha} Regulates the Expression of Glutathione S-transferase Genes and Modulates Acetaminophen-Glutathione Conjugation in Mouse Liver.
G. Dai, N. Chou, L. He, M. A. Gyamfi, A. J. Mendy, A. L. Slitt, C. D. Klaassen, and Y.-J. Y. Wan (2005)
Mol. Pharmacol. 68, 1590-1596
   Abstract »    Full Text »    PDF »
Retinoid X Receptor-{alpha}-Dependent Transactivation by a Naturally Occurring Structural Variant of Human Constitutive Androstane Receptor (NR1I3).
S. S. Auerbach, M. A. Stoner, S. Su, and C. J. Omiecinski (2005)
Mol. Pharmacol. 68, 1239-1253
   Abstract »    Full Text »    PDF »
Transcription coactivator peroxisome proliferator-activated receptor-binding protein/mediator 1 deficiency abrogates acetaminophen hepatotoxicity.
Y. Jia, G. L. Guo, S. Surapureddi, J. Sarkar, C. Qi, D. Guo, J. Xia, P. Kashireddi, S. Yu, Y.-W. Cho, et al. (2005)
PNAS 102, 12531-12536
   Abstract »    Full Text »    PDF »
In Vitro Zonation and Toxicity in a Hepatocyte Bioreactor.
J. W. Allen, S. R. Khetani, and S. N. Bhatia (2005)
Toxicol. Sci. 84, 110-119
   Abstract »    Full Text »    PDF »
Mechanistic Classification of Liver Injury.
J. M. Cullen (2005)
Toxicol Pathol 33, 6-8
   Abstract »    Full Text »    PDF »
Differential Expression of Mouse Hepatic Transporter Genes in Response to Acetaminophen and Carbon Tetrachloride.
L. M. Aleksunes, A. M. Slitt, N. J. Cherrington, M. S. Thibodeau, C. D. Klaassen, and J. E. Manautou (2005)
Toxicol. Sci. 83, 44-52
   Abstract »    Full Text »    PDF »
Enhanced Acetaminophen Toxicity by Activation of the Pregnane X Receptor.
G. L. Guo, J. S. Moffit, C. J. Nicol, J. M. Ward, L. A. Aleksunes, A. L. Slitt, S. A. Kliewer, J. E. Manautou, and F. J. Gonzalez (2004)
Toxicol. Sci. 82, 374-380
   Abstract »    Full Text »    PDF »
The Constitutive Androstane Receptor and Pregnane X Receptor Function Coordinately to Prevent Bile Acid-induced Hepatotoxicity.
J. Zhang, W. Huang, M. Qatanani, R. M. Evans, and D. D. Moore (2004)
J. Biol. Chem. 279, 49517-49522
   Abstract »    Full Text »    PDF »
Retinoid X Receptor {alpha} Regulates Glutathione Homeostasis and Xenobiotic Detoxification Processes in Mouse Liver.
Y. Wu, X. Zhang, F. Bardag-Gorce, R. C. V. Robel, J. Aguilo, L. Chen, Y. Zeng, K. Hwang, S. W. French, S. C. Lu, et al. (2004)
Mol. Pharmacol. 65, 550-557
   Abstract »    Full Text »    PDF »
A Novel Constitutive Androstane Receptor-Mediated and CYP3A-Independent Pathway of Bile Acid Detoxification.
S. P. S. Saini, J. Sonoda, L. Xu, D. Toma, H. Uppal, Y. Mu, S. Ren, D. D. Moore, R. M. Evans, and W. Xie (2004)
Mol. Pharmacol. 65, 292-300
   Abstract »    Full Text »    PDF »
Induction of Drug Metabolism: The Role of Nuclear Receptors.
C. Handschin and U. A. Meyer (2003)
Pharmacol. Rev. 55, 649-673
   Abstract »    Full Text »    PDF »
Carbon Monoxide Protects against Liver Failure through Nitric Oxide-induced Heme Oxygenase 1.
B. S. Zuckerbraun, T. R. Billiar, S. L. Otterbein, P. K.M. Kim, F. Liu, A. M.K. Choi, F. H. Bach, and L. E. Otterbein (2003)
J. Exp. Med. 198, 1707-1716
   Abstract »    Full Text »    PDF »
Use of a Low-Density Microarray for Studying Gene Expression Patterns Induced by Hepatotoxicants on Primary Cultures of Rat Hepatocytes.
F. de Longueville, F. A. Atienzar, L. Marcq, S. Dufrane, S. Evrard, L. Wouters, F. Leroux, V. Bertholet, B. Gerin, R. Whomsley, et al. (2003)
Toxicol. Sci. 75, 378-392
   Abstract »    Full Text »    PDF »
Decreased factor VIII levels during acetaminophen-induced murine fulminant hepatic failure.
C. B. Doering, E. T. Parker, C. E. Nichols, and P. Lollar (2003)
Blood 102, 1743-1744
   Abstract »    Full Text »    PDF »
Inactivation of the Hepatic Cytochrome P450 System by Conditional Deletion of Hepatic Cytochrome P450 Reductase.
C. J. Henderson, D. M. E. Otto, D. Carrie, M. A. Magnuson, A. W. McLaren, I. Rosewell, and C. R. Wolf (2003)
J. Biol. Chem. 278, 13480-13486
   Abstract »    Full Text »    PDF »
Induction of bilirubin clearance by the constitutive androstane receptor (CAR).
W. Huang, J. Zhang, S. S. Chua, M. Qatanani, Y. Han, R. Granata, and D. D. Moore (2003)
PNAS 100, 4156-4161
   Abstract »    Full Text »    PDF »
Activation of Orphan Nuclear Constitutive Androstane Receptor Requires Subnuclear Targeting by Peroxisome Proliferator-activated Receptor {gamma} Coactivator-1{alpha}: A POSSIBLE LINK BETWEEN XENOBIOTIC RESPONSE AND NUTRITIONAL STATE.
T. Shiraki, N. Sakai, E. Kanaya, and H. Jingami (2003)
J. Biol. Chem. 278, 11344-11350
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882