title: Thiols metabolism is altered by the herbicides paraquat, dinoseb and 2,4-D: a study in isolated hepatocytes.
abstract: This report is an extension and complement of a previous study reporting the effect of three herbicides (paraquat, dinoseb and 2,4-D) on cell 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 herbicides. Biochemical mechanisms of cytotoxicity induced by the herbicides paraquat (1,1'-dimethyl-4,4'-bipyridylium dichloride), dinoseb (2-sec-butyl-4,6-dinitrophenol) and 2,4-D (2,4-dichlorophenoxyacetic acid) were investigated in freshly isolated rat hepatocytes. Herbicide metabolism, 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, promote loss of protein thiol contents and induce lipid peroxidation. Dinoseb, the most effective cytotoxic compound under study (used in concentrations 1000-fold lower than paraquat and 2,4-D), had moderate effects upon the GSH/GSSG ratio and lipid peroxidation, causing a depletion of protein thiols of about 20%. The results indicate that the herbicides paraquat and 2,4-D are hepatotoxic and may induce cell death by decreasing cellular GSH/GSSG ratio and protein thiols, and by inducing lipid peroxidation. The cytotoxic action of dinoseb is likely to be related with the uncoupling of oxidative phosphorylation in mitochondria. Therefore, it is likely that liver damage observed during the first phase of herbicide-intoxication is related to these metabolic processes.
authors.affiliation: Department of Zoology, University of Coimbra, Portugal.
authors.forename: C M
authors.initials: CM
authors.lastname: Palmeira
authors.forename: A J
authors.initials: AJ
authors.lastname: Moreno
authors.forename: V M
authors.initials: VM
authors.lastname: Madeira
mesh_terms: D015084:2,4-Dichlorophenoxyacetic Acid / Q000633:toxicity*; D019297:2,4-Dinitrophenol / Q000031:analogs & derivatives*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004140:Dinitrophenols / Q000633:toxicity*; D005978:Glutathione / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D019803:Glutathione Disulfide; D006540:Herbicides / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010269:Paraquat / Q000633:toxicity*; D051381:Rats; D013438:Sulfhydryl Compounds / Q000378:metabolism*
chemical_list: D004140:Dinitrophenols; D006540:Herbicides; D013438:Sulfhydryl Compounds; D015084:2,4-Dichlorophenoxyacetic Acid; D000255:Adenosine Triphosphate; D005978:Glutathione; D010269:Paraquat; D019297:2,4-Dinitrophenol; D019803:Glutathione Disulfide; C018527:dinoseb