Molecular basis for the activity of nickel.

The molecular mechanism for the carcinogenic activity of nickel has been investigated in vitro and in vivo. Formation of stable ternary nickel (II)-DNA-protein complexes occurred in vitro upon incubation of nickel subsulfide (Ni3S2) with DNA and microsomes in 0.05 M tris hydrochloride, pH 7.4. DNA damage in the form of strand breaks and DNA-protein cross-links resulted in vivo following injection of nickel carbonate in rats. Kidney was the preferred tissue for nickel accumulation and DNA damage. A gentle isolation procedure was developed for the isolation of nucleic acids containing bound nickel from tissues of rats injected with nickel carbonate. Higher levels of nickel were bound to kidney nucleic acids as compared with liver nucleic acids. The amount of protein associated with kidney and liver DNA correlated with the amount of nickel bound. Removal of protein associated with kidney DNA and RNA resulted in reduction of the amount of nickel bound. Nickel levels remained constant upon removal of associated protein from liver DNA, but were reduced upon removal of protein from liver RNA. These results are discussed relative to the known carcinogenicity, solubilization and aqueous chemistry of nickel compounds.