Investigations have continued to test two hypotheses on molecular mechanisms of nickel carcinogenesis: (1) nickel initiates tumors by damaging DNA with oxygen species activated by nickel redox catalysis; and (2) nickel promotes tumors and assists in their progression through interference with the functions of essential divalent metals. Relative to hypothesis (1), increased contents of 8-hydroxy-2'deoxyguanosine (8-OHdG) were found in DNA isolated from NIH 3T3 cells and from organs of rats exposed to Ni(II). Thus, unlike cell-free in vitro models, Ni(II)-complexing agents cannot prevent enhancement by nickel of the DNA-bound 8-OHdG formation in living cells. Localized radical reaction at the cell nuclei is therefore postulated. Another genotoxic effect of Ni(II), deamination of DNA bases, has been confirmed in NIH 3T3 cells. Oxidative effects of nickel on DNA and other molecules may be strengthened by inhibition of glutathione (GSH), glutathione peroxidase (GSH-Px), and/or catalase (CAT). Mice of strains rich in GSH were less sensitive to Ni(II)-induced lipid peroxidation (LPO) and lethality than mice with lower tissue levels of those agents. Correlation between CAT and LPO was less evident. Similar relations were found in rats. Hence, GSH and GSH-Px seem to be stronger inhibitors of nickel-induced oxidative damage than is CAT. Testing of hypothesis No. 2 has continued on the renal carcinogenesis model. Nickel-induced renal tumors in F344 rats could be prevented with magnesium (Mg) but not iron (Fe). Thus, in concordance with our previous results in muscle and lungs, the effectiveness of Mg in counteracting nickel carcinogenesis has been confirmed in yet another tissue. However, contrary to our findings in muscle, Fe greatly enhanced renal carcinogenesis by nickel. The K-ras oncogene was found activated in 11 of 16 renal tumors induced by nickel; point mutation consisting of G-T transversion at the second position of codon 12 of this oncogene was discovered, thus providing further evidence that DNA guanine is the main target molecule for nickel genotoxicity (see Project Z01CP05399).
