The induction of tumor necrosis factor-alpha, superoxide anion, myeloperoxidase, and superoxide dismutase in the peritoneal lavage cells of mice after prolonged exposure to dichloroacetate and trichloroacetate
The induction of phagocytic activation in response to prolonged treatment with different doses of dichloroacetate (DCA) and trichloroacetate (TCA) has been investigated in mice. Groups of B6C3F1 male mice were administered 7.7, 77, 154, and 410 mg of DCA or TCA/kg/day, postorally, for 4- and 13-weeks. Peritoneal lavage cells (PLCs) were isolated and assayed for the different biomarkers of phagocytic activation, including superoxide anion (SA), tumor necrosis factor-alpha (TNF-alpha), and myeloperoxidase (MPO). In addition, the role of superoxide dismutase (SOD) in the SA production was also assessed. DCA and TCA produced significant and dose-dependent increases in SA and TNF-alpha production and in MPO activity, but the increases in response to the high doses of the compounds (>77 mg/kg/day) in the 13-week treatment period were less significant than those produced in the 4-week treatment period. Also, dose-dependent increases in SOD activity were observed in both periods of treatments. In general, the results demonstrate significant induction of the biomarkers of phagocytic activation by doses of DCA and TCA that were previously shown to be noncarcinogenic, with significantly greater increases observed at the earlier period of exposure, as compared with later period. These findings may argue against the contribution of those mechanisms to the hepatotoxicity/hepatocarcinogenicity of the compounds and suggest them to be early adaptive/ protective mechanisms against their long-term effects.