TRANSITION-METAL MEDIATED FREE RADICAL FORMATION IN VITRO AND IN VIVO

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Although free radical formation is known to occur from cooper in Fenton- like reactions in vitro, free radicals from copper have not been detected in living animals until now. By applying ESR and the secondary radical spin trapping technique, evidence for hydroxyl radical formation in vivo was obtained in rats treated simultaneously with copper and ascorbic acid. The existence of hydroxyl radical has also been shown in the file of selenium- and vitamin E-deficient rats during conditions of acute copper overload. We demonstrate that hydroxyl radical generated by copper can indeed occur in vivo and contribute to oxidative damage, though in our model of copper-intoxicated rats copper alone does not cause the formation of detectable radical adducts. Paraquat is a toxin whose toxicity is attributed to its ability to generate the superoxide radical anion. Increased superoxide production can in turn stimulate hydroxyl radical formation in vitro and in vivo from metal ions. We have shown this to be true for both copper and iron overload experiments in rats. Some metal ions may also have beneficial effects on free radical metabolites in vivo. Our results show a suppression of free radical metabolites detected in rats from the metabolism of the hepatotoxin carbon tetrachloride due to pretreatment with trivalent chromium. The formation of artifactual radical adducts in spin trapping experiments is a possibility that must always be guarded against. We have demonstrated experimental procedures necessary to inhibit ex vivo metal ion-induced free radical chemistry in cases of metal overload. This is crucial for correctly identifying radicals generated in vivo. We have established certain criteria for suppressing artifactual ESR signals in vitro resulting from non-radical chemistry of the spin trap DMPO in the presence of copper and iron ions.