Potential toxicity of toluene and xylene evoked by mitochondrial uncoupling

Toluene and xylene are chemicals present in various laboratory and other industrial products. Their toxicity to the nervous system and to the liver has been well documented. In the present work, we have studied in vitro effects of toluene and xylene on the respiration of succinate-energized isolated rat liver mitochondria, membrane potential, Ca2+ release, reactive oxygen species (ROS), and ATP levels. Also Ca2+-dependent, cyclosporine A-sensitive mitochondrial swelling, an indicator of mitochondrial permeability transition (MPT), was studied. At 0.5-2.5 and 0.25-1mM concentrations respectively, toluene and xylene stimulated state 4 respiration in apparent association with mitochondrial membrane potential dissipation and Ca2+ release; these actions of both solvents are consistent with mitochondrial uncoupling. At higher concentrations (2.5 and 5mM, respectively) toluene and xylene also inhibited state 3 respiration. At 0.1-1mM concentrations, xylene elicited significant increase of ROS generation and partly Ca2+-dependent cyclosporine A-sensitive mitochondrial swelling. At 1 mM concentration, toluene or xylene caused depletions of mitochondrial ATP, amounting to 66.3% and 40.3%, respectively; depletions were only slightly dependent on Ca2+. It was concluded that mitochondrial uncoupling via ATP depletion might be responsible for the cell toxicity of toluene described earlier and in particular, of xylene. In the case of xylene, mitochondrial ROS generation and MPT also appear to be involved.