ToxSci Advance Access originally published online on August 12, 2003
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Toxicological Sciences 76, 201-211 (2003)
Copyright © 2003 by the Society of Toxicology
SYSTEMS TOXICOLOGY |
The Role of Hepatocellular Oxidative Stress in Kupffer Cell Activation during 1,2-Dichlorobenzene-Induced Hepatotoxicity
* Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721; and
Department of Medical Pharmacology and Toxicology, Texas A&M University System Health Science Center, College Station, Texas 77843
1,2-Dichlorobenzene (1,2-DCB), an industrial solvent, is a known hepatotoxicant. Two oxidative events in the liver contribute to 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 inflammatory cascade. To investigate the molecular effects of 1,2-DCB, primary cultures of Fischer-344 (F-344) and Sprague-Dawley (SD) rat hepatocytes were incubated with 1,2-DCB (3.6–12.4 µmol) and examined for enhanced DNA-binding activity of the oxidant-sensitive transcription factors activator protein–1 (AP-1), nuclear factor-kappa B (NF-
B), and electrophile responsive element (EpRE), and production and release of the chemokine cytokine-induced neutrophil chemoattractant (CINC). In F-344 rat hepatocytes, the activities of AP-1 and NF-B were increased by as much as 3-fold by 6 h of 1,2-DCB treatment, when compared to control. Nuclear translocation of EpRE was also enhanced by 3-fold and occurred 2 h 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-B-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.
Key Words: Kupffer cell; Fischer-344 rat; Sprague-Dawley rat; 1,2-dichlorobenzine.