Dichloroacetate‐induced modulation of cellular antioxidant enzyme activities and glutathione level in the J774A.1 cells

Abstract

Dichloroacetate (DCA) is used for different medical and industrial purposes and has been found to be a toxic by-product produced during the process of water chlorination. The DCA effects on superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) activities and glutathione (GSH) level were assessed and correlated with each other and also with cellular viabilities in J774A.1 macrophage cells. A concentration of 24 mm of DCA resulted in time-dependent decreases in cellular viability and glutathione level, and time-dependent increases in SOD activity when incubated with the cells for 24-48 h. DCA also resulted in significant increases in CAT and GSH-Px activities of the viable cells when incubated with the cells for 36 and 48 h. The changes in antioxidant enzyme activities and GSH levels were found to be strongly correlated with each other, and with cellular viabilities at different time points. While GSH did not result in any significant effects when added to the cells at concentrations ranging between 15 and 60 nmol ml(-1), it resulted in concentration-dependent increases in cellular viability when added to the DCA-treated cells, with maximal effects achieved at 45-60 nmol GSH ml(-1). However, cellular viability of the GSH + DCA treated cells remained below that of the control. Since viable cells from the DCA-treated cultures displayed significantly higher antioxidant enzyme activities compared with the control, it is concluded that those increases may have contributed to the cellular protection against DCA-induced cell death. Also, glutathione depletion has a major contribution to the observed cellular death induced by DCA.

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 results of this study also differ from those of in vitro studies showing an association between SA production and cellular death induced by DCA and TCA on macrophage cell culture. These differences are clearly related to the toxicokinetic of the compounds in an in vivo , as compared with an in vitro system (32–34)…”

“…In vitro studies on the effects of the compounds in the J774A.1 macrophage cells have also assessed the protective effects of antioxidant enzymes and TNF antibodies against the compounds’-induced SA production (33–34). Recent studies have demonstrated the production of phagocytic activation in the peritoneal lavage cells (PLCs) of B6C3F1 male mice, several hours after exposure to single high doses of DCA and TCA (18).…”

Lactic acid in cancer and mitochondrial disease

“…It is also being evaluated for the treatment of cancer [Michelakis et al, 2008;Bonnet et al, 2007]. Unfortunately, however, DCA is toxic [Shroads et al, 2008;Hassoun and Mehta, 2008]. It is taken up by the mitochondria of both normal and abnormal cells, and once located within mitochondrial membranes is routinely metabolized by the mitochondria into oxalic acid, a substance that, like lactic acid, is toxic to many cell types when over-produced, particularly neurons Aicher et al, 1999].…”

Dichloroacetate Decreases Cell Health and Activates Oxidative Stress Defense Pathways in Rat Alveolar Type II Pneumocytes

“…Until this time, however, the effect of DCA on type I or type II pneumocytes has not been reported. Type II cells secrete pulmonary surfactant, and, in response to lung damage, proliferate and differentiate into the type I pneumocytes that are responsible for gas exchange [ 31 , 32 ]. Damage to type II pneumocytes is highly detrimental to lung function and, thus, understanding DCA's effects in type II pneumocytes is critical to the evaluation of its toxicological impact.…”