A mechanism of paraquat toxicity in mice and rats

Abstract

The purpose of this study was to investigate the hypothesis that paraquat toxicity results from cyclic reduction-oxidation of paraquat in vivo, with subsequent generation of superoxide radicals and initiation of lipid peroxidation. Phenobarbital pretreatment (0.1% in drinking water for 10 days) significantly increased the paraquat LD50 in mice, but only when the mice were continued on phenobarbital after paraquat administration. Phenobarbital, through its own metabolism, may be competing for electrons which might otherwise be utilized in paraquat reduction and thus decrease paraquat toxicity. Paraquat, given at 30 mg/kg ip to mice, significantly decreased liver concentrations of the water-soluble antioxidant, reduced glutathione, and lung concentrations of lipid-soluble antioxidants. The decrease in tissue antioxidants may reflect the initiation of lipid peroxidation by paraquat. Oxygen-tolerant rats (exposure to 85% oxygen for 7 days) have increased activities of pulmonary enzymes which combat lipid peroxidation. The paraquat Lt50 (median time to death) after 45 mg/kg of paraquat ip was significantly increased in oxygentolerant rats compared to room-air-exposed controls. Rats exposed to 100 ppm paraquat in the drinking water for 3 weeks had significantly elevated activities of lung glucose-6-phosphate dehydrogenase and glutathione reductase. The cross-tolerance of oxygen and paraquat and the induction by paraquat of pulmonary enzymes that supply reducing equivalents to combat oxidative damage support the proposal that paraquat may initiate lipid peroxidation in vivo.