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

Abstract

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 , post orally, for 4-and 13-weeks. Peritoneal lavage cells (PLCs) were isolated and assayed for the different biomarkers of phagocytyic activation, including superoxide anion (SA), tumor necrosis factor-alpha (TNF-α), 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-α 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 non carcinogenic, 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.

The Effects of Mixtures of Dichloroacetate and Trichloroacetate on Induction of Oxidative Stress in Livers of Mice After Subchronic Exposure

“…The reported elevation was not statistically significant, but was close to the 1.3 fold increase previously shown to be associated with hepatomegaly and reduction in biomarkers of OS induced by 410 mg DCA/kg/day in subchronic studies [Hassoun et al, 2010a]. Previously Hassoun et al (2010b) indicated a protective role of phagocytic activation against chronic DCA- and TCA-induced hepatotoxicity and that mixtures of compositions similar to Mix I and II produced additive effects on this mechanism. However, a mixture of similar composition to Mix III resulted in less than additive effects [Hassoun et al, 2013].…”

“…Dose-dependent increases in tinduction of hepatic superoxide anion (SA), lipid peroxidation (LP) levels and DNA damage in response to subchronic doses of DCA and TCA ranging from 7.7–410 mg/kg/day mg/kg/day, with maximal elevation in induction of those biomarkers achieved by DCA and TCA daily doses of 154 and 410 mg/kg/day, respectively [Hassoun et al, 2010a]. The induction of hepatic OS after sub-chronic exposure of mice to DCA and TCA was also shown to be associated with induction of phagocytic activation in the same animals [Hassoun et al, 2010b]. Since humans experience life-time exposure to mixtures rather than individual compounds, and the outcome of toxicity levels in response to mixtures may vary from those induced by individual compounds, studies on chronic effects of mixtures of the compounds is important.…”

Vitamin E restriction in the diet enhances phagocytic activation by dichloroacetate and trichloroacetate in mice

“…Previous sub-chronic studies on B 6 C 3 F 1 mice found this dose to also induce maximal levels of SA, TNFα, and MPO activity in their PLC (Hassoun et al, 2010b), but no apparent hepatomegaly (Hassoun et al, 2010a). …”

“…Both compounds also modulated the levels of various biomarkers of phagocytic activation in the PLC of mice and this activation was suggested to be an early adaptive/protective mechanism against their long term hepatotoxic/ hepatocarcinogenic effects (Hassoun et al, 2010b). …”

“…The vitamin also plays an important role in immune system maintenance (de La Fuente et al, 1998, 2000; reviewed in Feki et al [2001], Han et al [2004], and Castellani et al [2010]). In an attempt to investigate the role of this anti-oxidant in the induction of phagocytic activation by DCA and TCA (that was previously suggested to play a role in their associated hepatotoxicity; Hassoun et al, 2010b), the extent of activation induced by each agent was determined in the PLC from B 6 C 3 F 1 mice fed (for 13 weeks) a standard chow diet (Std-diet group) or a diet not supplemented with the vitamin, but with the vitamin present as a component of other natural ingredients in the feed (Low-E diet group).…”