MECHANISMS FOR ALTERING PARAQUAT TOXICITY

本研究的目的是探讨其机制

The purpose of the proposed study is to investigate the mechanisms by which paraquat's prooxidant toxicity can be prevented through prophylactic treatment with novel chemical agents. Although the use of superoxide dismutase has been widely reviewed in the literature, few other interactions have been examined except for diet modification or nutritional deficiencies. Although extensive publications on paraquat exist, no antidotal therapies short of hemodialysis or blood replacement appear to be effective. Experiments in the chicken and the mouse have indicated negative interactions between arthritis medications and prooxidant chemicals, such as paraquat. Prevention of paraquat toxicity is accomplished through dietary addition of Ebselen, a novel anti- inflammatory agent with glutathione peroxidase activity or simultaneously administered penicillamine. Preliminary experiments in the mouse indicate 1) Low dose prevention of paraquat toxicity by penicillamine and high dose enhanced lethality, 2) an unexpected substantial protection of intramuscularly injected corn oil against oral paraquat, and 3) reversal of corn oil's protective effect by high intramuscular doses of Ebselen in corn oil. The present study will concentrate on the last two factors to determine the role of injected oils and injected versus oral Ebselen on paraquat toxicity in the mouse to understand the mechanisms which define their antidotal versus toxic interactions with paraquat. Expected experiments are 1) effects of corn oil and other linoleic- polyunsaturated oils on paraquat toxicity, 2) influence of oral versus injected Ebselen on paraquat toxicity, 3) alterations in paraquat pharmacokinetics by Ebselen and corn oil, especially in intestine/plasm and plasma/lung, and 4) modification of paraquat toxicity by cyclooxygenase and lipoxygenase inhibition with and without corn oil both as a control for the lipoxygenase inhibition with and without corn oil both as a control for the lipoxygenase inactivation effects of Ebselen and possible effects of injected corn oil on lung prostaglandins and leukotrienes.