Investigations of the effects of essential divalent metals, Mg, Ca, Zn, and Fe, on the carcinogenicity of Ni have been continued in bioassay and biochemical studies aimed at elucidation of the mechanisms of nickel carcinogenesis. The results indicate that Mg, Ca, and possibly Fe, affect transmembrane transport of Ni and greatly modify local inflammatory/immune response to nickel carcinogens, especially by macrophages, whereas Zn, a much weaker antagonist, has no effect on Ni transport and no detectable influence on the local immune response, including macrophage activation. Ni/Ca interactions have been studied with calmodulin. Ni binds to calmodulin in the presence of Ca; two binding sites are involved. Thus Ni may interfere with regulatory functions of the Ca-calmodulin complex. The disruption of cell-cell communication in 3T3 cells, shown last year, indicated some tumor-promotional activity o. this metal. Subsequently, a bioassay to test promotional activity of Ni toward renal tumors initiated with methyl(methoxymethyl)nitrosoamine is underway. Following the observations of local inflammatory/immune responses to Ni and the other metals, a study on possible involvement of active oxygen species and related enzymatic systems in nickel carcinogenesis has been undertaken. Three important effects of nickel subsulfide (Ni3S2), the strongest nickel carcinogen, have been discovered: (1) Ni3S2 and Ni(II) derived by oxidative dissolution of Ni3S2, inhibit enzymatic activity of catalase and glutathione peroxidase; (2) Ni3S2 in the presence of oxygen causes polymerization of histones in calf thymus nucleohistone in vitro; this reaction is enhanced by small peptides and/or hydrogen peroxide; (3) Ni3S2 in the presence of oxygen causes oxidation of 2'-deoxyguanosine to potentially mutagenic 8-hydroxy-2'deoxyguanosine in vitro. Effects (2) and (3) suggest that Ni3S2, a supposedly nongenotoxic carcinogen, is, in fact, capable of damaging cellular genetic material. Effect (1) is contributory to the other two. Thus, for the first time a close resemblance was found between the action of Ni3S2 and that of classical carcinogens.
