Role of nuclear receptor CAR in carbon tetrachloride-induced hepatotoxicity

doi:10.3748/wjg.v11.i38.5966

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Oct 14, 2005 (publication date) through Nov 24, 2024

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Basic Research

World J Gastroenterol. Oct 14, 2005; 11(38): 5966-5972
Published online Oct 14, 2005. doi: 10.3748/wjg.v11.i38.5966

Role of nuclear receptor CAR in carbon tetrachloride-induced hepatotoxicity

Yuichi Yamazaki, Satoru Kakizaki, Norio Horiguchi, Hitoshi Takagi, Masatomo Mori, Masahiko Negishi

Yuichi Yamazaki, Satoru Kakizaki, Norio Horiguchi, Hitoshi Takagi, Masatomo Mori, Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan

Masahiko Negishi, Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA

Author contributions: All authors contributed equally to the work.

Supported by a Grant-in Aid for Scientific Research, No. 15790337 from the Ministry of Education, Science, Sports and Culture of the Japanese Government

Correspondence to: Satoru Kakizaki, MD, PhD, Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi 371-8511, Japan. kakizaki@showa.gunma-u.ac.jp

Telephone: +81-27-220-8127 Fax: +81-27-220-8136

Received: March 25, 2005
Revised: April 23, 2005
Accepted: April 30, 2005
Published online: October 14, 2005

Abstract

AIM: To investigate the precise roles of CAR in CCl₄-induced acute hepatotoxicity.

METHODS: To prepare an acute liver injury model, CCl₄- induced was intraperitoneally injected in CAR^+/+ and CAR^-/- mice.

RESULTS: Elevation of serum alanine aminotransferase and extension of centrilobular necrosis were slightly inhibited in CAR^-mice compared to CAR^+/+ mice without PB. Administration of a CAR inducer, PB, revealed that CCl₄-induced liver toxicity was partially inhibited in CAR^-/- mice compared with CAR^+/+ mice. On the other hand, androstanol, an inverse agonist ligand, inhibited hepatotoxicity in CAR^+/+ but not in CAR^-/- mice. Thus, CAR activation caused CCl₄- induced hepatotoxicity while CAR inhibition resulted in partial protection against CCl₄-induced hepatotoxicity.There were no differences in the expression of CYP2E1, the main metabolizing enzyme for CCl₄, between CAR^+/+ and CAR^-/- mice. However, the expression of other CCl₄-metabolizing enzymes, such as CYP2B10 and 3A11, was induced by PB in CAR^+/+ but not in CAR^-/- mice. Although the main pathway of CCl₄-induced acute liver injury is mediated by CYP2E1, CAR modulates its pathway via induction of CYP2B10 and3A11 in the presence of activator or inhibitor.

CONCLUSION: The nuclear receptor CAR modulates CCl₄-induced liver injury via induction of CCl₄-metabolizing enzymes in the presence of an activator. Our results suggest that drugs interacting with nuclear receptors such as PB might play critical roles in drug-induced liver injury or drug-drug interaction even though such drugs themselves are not hepatotoxic.

Keywords: CAR; Phenobarbital; Cytochrome P450; CCl₄; Drug-induced liver injury