THIOLS METABOLISM IS ALTERED BY THE HERBICIDES PARAQUAT, DINOSEB AND 2,4-D - A STUDY IN ISOLATED HEPATOCYTES

This report is an extension and complement of a previous study reporti ng the effect of three herbicides (paraquat, dinoseb and 2,4-D) on cel l viability, GSH oxidation, NADH and ATP depletion (Arch. Toxicol. 68: 24-31, 1994). Here we report additional data and findings aimed at a better understanding of the toxicity mechanisms induced by these herbi cides. Biochemical mechanisms of cytotoxicity induced by the herbicide s paraquat (1,1'-dimethyl-4,4'-bipyridylium dichloride), dinoseb (2-se c-butyl-4,6-dinitrophenol) and 2,4-D (2,4-dichlorophenoxyacetic acid) were investigated in freshly isolated rat hepatocytes. Herbicide metab olism, especially paraquat and 2,4-D, rapidly depletes GSH and protein thiols. Paraquat and 2,4-D (1-10 mM) decrease the GSH/GSSG ratio, pro mote loss of protein thiol contents and induce lipid peroxidation. Din oseb, the most effective cytotoxic compound under study (used in conce ntrations 1000-fold lower than paraquat and 2,4-D), had moderate effec ts upon the GSH/GSSG ratio and lipid peroxidation, causing a depletion of protein thiols of about 20%. The results indicate that the herbici des paraquat and 2,4-D are hepatotoxic and may induce cell death by de creasing cellular GSH/GSSG ratio and protein thiols, and by inducing l ipid peroxidation. The cytotoxic action of dinoseb is likely to be rel ated with the uncoupling of oxidative phosphorylation in mitochondria. Therefore, it is likely that liver damage observed during the first p hase of herbicide-intoxication is related to these metabolic processes .