Studies on molecular mechanism of nickel (Ni) carcinogenesis have been continued in both in vivo and in vitro systems. The studies have been focused on testing the hypothesis that Ni initiates tumors by generating active oxygen species that damage DNA. Our major findings have been the following: (1) Ni cation, which by itself is not redox active under physiological conditions, becomes redox active if complexed with physiological oligopeptides and/or amino acids, i.e., by ligands that serve as tissue Ni carriers; the resulting complexes may catalyze redox reactions of DNA and nuclear proteins with molecular oxygen and/or hydrogen peroxide leading to oxidation of DNA bases, guanine in particular. (2) The enhancement by Ni of the oxidation of guanine residues in 2'-deoxyguanosine (dG) to its 8-hydroxy derivative (8-OH-dG) cannot be prevented by natural antioxidants, including glutathione and ascorbic acid; this explains the presence of 8-OH-dG and other modified DNA bases discovered by us in kidneys of Ni-treated rats. (3) Parenteral administration of Ni to pregnant rats initiates sodium barbital- promotable renal tumors in the male offspring and produces pituitary gland tumors in male and female offspring. (4) Eleven oxidatively modified DNA bases were identified and measured in renal chromatin of the dams and fetuses 1 to 2 days after Ni treatment. Ni treatment-related increase in the amounts of some of these bases found may indicate possible involvement of DNA base oxidation in the initiation step of Ni carcinogenesis in the rat kidney.
