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ToxSci Advance Access published online on August 12, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg207
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received May 16, 2003; accepted July 20, 2003
© 2003 Society of Toxicology

Systems Toxicology

The Role of Hepatocellular Oxidative Stress in Kupffer Cell Activation During 1,2-Dichlorobenzene Induced Hepatotoxicity

Husam S. Younis 1, Alan R. Parrish 2, and I. Glenn Sipes 1*

1 Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ
2 Department of Medical Pharmacology & Toxicology, Texas A&M University System Health Science Center, College Station, TX

* To whom correspondence should be addressed. E-mail: sipes{at}email.arizona.edu.


  Abstract

1,2-Dichlorobenzene (1,2-DCB), an industrial solvent, is a known hepatotoxicant. Two oxidative events in the liver contribute to 1,2-Dichlorobenzene (1,2-DCB) induced liver injury; an initial hepatocellular oxidative stress followed by oxidant stress associated with an inflammatory response. We hypothesize that the initial hepatocellular oxidative event triggers molecular and cellular processes within hepatocytes that lead to the production of factors that contribute to Kupffer cell (KC) activation and upregulation of the inflammatorycascade. To investigate the molecular effects of 1,2-DCB, primary cultures of F-344 and SD rat hepatocytes were incubated with 1,2-DCB (3.6-12.4 umol) and examined for enhanced DNA binding activity of the oxidant sensitive transcription factors AP-1, NF-kB and EpRE and production and release of the chemokine CINC. In F-344 rat hepatocytes, the activities of AP-1 and NF-kB were increased by as much as 3-fold by 6 hr of 1,2-DCB treatment as compared to control. Nuclear translocation of EpRE was also enhanced by 3-fold and occurred 2 hr following 1,2-DCB treatment. These events were greater in F-344 than in SD rat hepatocytes incubated with 1,2-DCB. Moreover, F-344 rat hepatocytes produced and released CINC following incubation with 1,2-DCB but SD rat hepatocytes did not. Lastly, conditioned media from 1,2-DCB treated F-344 rat hepatocytes stimulated KC activity as determined by enhanced NF-kB binding activity and increased nitric oxide production. Collectively, these data suggest that the mechanisms of 1,2-DCB-induced hepatotoxicity involve intercellular communication whereby compromised hepatocytes may signal KC activation via the production and release of oxidant sensitive chemokines and cytokines.


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