Studies focused on testing the hypothesis that nickel (Ni) initiates tumors through generation of DNA-damaging free radicals have been continued in chemical and animal models. The following results were obtained. (1) Histidine, a physiological Ni carrier, was found to greatly enhance Ni-mediated in vivo DNA-protein cross-linking, DNA strand breaking, and oxidative nucleobase damage in the rat kidney, the target organ for nickel carcinogenicity. (2) Histidine was shown to enhance oxidative production of oxygen- and carbon-centered radicals from Ni-cysteine complex, another tissue Ni carrier. Formation of such radicals, originating from both amino acids involved, may explain preferential DNA cross-linking with histidine and cysteine residues of proteins in nickel-treated cells. (3) Model lipid hydroperoxides were found to be capable of reacting in vitro with some Ni-oligopeptide complexes to produce a variety of radical species originating from both the oligopeptides and the peroxides. Such radicals may be responsible for DNA adduct formation and cross-linking effects. (4) Oxidative generation of two kinds of free radicals, produced by both constituents of the nickel subsulfide molecule (Ni3S2), was established. Combination of the genotoxic effects of those radicals may be responsible for the high carcinogenic potency of Ni3S2. (5) Production of free radicals from hydrogen peroxide and lipid peroxides by carcinogenic chromium and cobalt compounds has been studied for comparative reasons and shown to occur under physiological conditions. The observed differences in identity and quantity of free radicals produced by various metals helps to explain the different carcinogenic potentials of those metals (see also project Z01CP05352).
