The molecular and cellular mechanisms of 1,2-dichlorobenzene induced liver injury in Fischer-344 and Sprague-Dawley rats

1,2-Dichlorobenzene (1,2-DCB), an industrial solvent, is a potent hepatotoxicant in Fischer-344 (F-344) rats. Bioactivation of 1,2-DCB by cytochrome P450 enzymes in the liver and subsequent activation of Kupffer cells (KC), the resident liver macrophages, are required for the development and progression of liver damage. The mechanisms by which KC cells become activated in chemical induced liver injury are unknown. The studies described in this dissertation utilized 1,2-DCB as a model hepatotoxicant to test the hypothesis that KC activation following 1,2-DCB induced liver injury is triggered by molecular and cellular events in hepatocytes that lead to the expression of proteins known to activate inflammatory cells. The administration of 1,2-DCB (3.6mmol/kg, i.p.) to F-344 rats or incubation of 1,2-DCB (3.6 umol) with primary cultured hepatocytes of F-344 rats produces an intracellular oxidative stress as assessed by the production of glutathione disulfide. The binding activity of transcription factors associated with oxidative stress (AP-1, EpRE and NF-kB) were also enhanced in F-344 rat hepatocytes by 2 to 6 hr of incubation with 1,2-DCB. After 12 hr of incubation with 1,2-DCB, the production and release of CINC was 2.2-fold greater in F-344 rat hepatocytes than control cells. The mRNA expression of the chemokine MIF was also increased by 1,2-DCB in F-344 rat hepatocytes. In contrast, these molecular and cellular events were delayed or significantly reduced in the hepatocytes of the Sprague-Dawley rat, which is much less sensitive to 1,2-DCB induced hepatotoxicity. Furthermore, KC incubated with conditioned media from F-344 rat hepatocytes treated with 1,2-DCB for 24 hr showed enhanced NF-kB binding activity. Interestingly, the receptor for CINC, CXC Receptor 2, was expressed on KC as determined by immunohistochemical analysis. These data suggest that hepatocellular oxidative stress may trigger a cascade of molecular processes in hepatocytes that promote the expression and release of oxidant sensitive chemokines. These products signal the activation of KC and the upregulation of the inflammatory response leading to the progression of 1,2-DCB induced liver damage