Paraquat toxicity: proposed mechanism of action involving lipid peroxidation.
The purpose of this study was to investigate the hypothesis that paraquat pulmonary toxicity results from cyclic reduction-oxidation of paraquat with sequential generation of superoxide radicals and singlet oxygen and initiation of lipid peroxidation. In vitro mouse lung microsomes catalyzed an NADPH-dependent, single-electron reduction of paraquat. Incubation of paraquat with NADPH, NADPH-cytochrome c reductase, and purified microsomal lipid increased malondialdehyde production is a concentration dependent manner. Addition of either superoxide dismutase or a single oxygen trapping agent 1,3-dipheylisobenzo furan inhibited paraquat stimulated lipid peroxidation. In vivo, pretreatment of mice with phenobarbital decreased paraquat toxicity, possibly by competing for electrons which might otherwise reduce paraquat. In contrast, paraquat toxicity in mice was increased by exposure to 100% oxygen and by deficiencies of the antioxidants selenium, vitamin E, or reduced glutahione (GSH). Paraquat, given IP to mice, at 30 mg/kg, decreased concentrations of the water-soluble antioxidant GSH in liver and lipid soluble antioxidants in lung. Oxygen-tolerant rats, which hae increased activities of pulmonary enzymes which combat lipid peroxidation, were also tolerant to lethal doses of paraquat as indicated by an increased paraquat LT50. Furthermore, rats chronically exposed to 100 ppm paraquat in the water had elevated pulmonary activities of glucose-6-phosphate dehydrogenase and GSH reductase. These results were consistent with the hypothesis that lipid peroxidation is involved in the toxicity of paraquat.
D000693:Anaerobiosis; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D005609:Free Radicals; D005980:Glutathione Reductase / Q000378:metabolism; D007928:Lethal Dose 50; D050356:Lipid Metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000494:pharmacology; D010269:Paraquat / Q000378:metabolism / Q000633:toxicity*; D010545:Peroxides / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D013482:Superoxide Dismutase / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D005609:Free Radicals; D010545:Peroxides; D014810:Vitamin E; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D010269:Paraquat; D010100:Oxygen; D010634:Phenobarbital