The role of metabolic activation and oxidant injury in the hepatotoxicity of 1,2-dichlorobenzene in the rat
Committee ChairSipes, I. Glenn
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PublisherThe University of Arizona.
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Abstract1,2-Dichlorobenzene (1,2-DCB) is a potent hepatotoxicant in the Fischer-344 (F344) rat. Phenobarbital (PB), a known inducer of cytochrome P-450, enhanced the metabolism and covalent binding of 1,2-DCB in F344 rat liver microsomes. Identification of 2,3-dichlorophenol, 3,4-dichlorophenol and dichlorobenzene dihydrodiol indicated the formation of dichlorobenzene epoxides in PB induced microsomes. Moreover, modulation of microsomal metabolism and covalent binding using glutathione, trichloropropene oxide, ascorbic acid and superoxide dismutase implicated quinones as the major covalent binding species of 1,2-DCB. These findings indicate that 1,2-DCB is activated by cytochrome P-450 to reactive intermediates that may initiate hepatocellular injury. The hepatotoxicity of 1,2-DCB was also studied in normal F344 rats administered methyl palmitate (MP) to inhibit Kupffer cell function or superoxide dismutase (conjugated to polyethylene glycol, i.e. PEG-SOD) to scavenge superoxide anions. Both agents markedly reduced the severity of 1,2-DCB induced liver injury in normal rats. However, MP and PEG-SOD did not inhibit the PB potentiated hepatotoxicity of 1,2-DCB. In summary, the data presented in this dissertation strongly support a role for Kupffer cell derived superoxide anions in the hepatotoxicity of 1,2-DCB in normal F344 rats. Since Sprague-Dawley (SD) rats are less susceptible to the hepatotoxicity of 1,2-DCB than F344 rats, markers of oxidant injury were assessed in both strains of rats following administration of 1,2-DCB. 1,2-DCB treatment did not deplete hepatic vitamin E in F344 or SD rats. However, 1,2-DCB treated F344 rats exhibited greater ethane exhalation than SD rats, at a time when differences in GSH depletion between the two strains were most prominent and prior to the initial appearance of toxicity in F344 rats. The results further confirmed the involvement of oxidative injury in the hepatotoxicity of 1,2-DCB. It is concluded that two key events are involved in the hepatotoxicity of 1,2-DCB (1) metabolism of 1,2-DCB by cytochrome P-450 to reactive intermediates that initiate cell injury (2) oxidative injury induced by Kupffer cell derived active oxygen species, that contributes to the progression of the injury.
Degree ProgramPharmacology & Toxicology