A POSSIBLE ROLE FOR CHROMIUM(III) IN GENOTOXICITY

Chromium is found in the environment in two major forms: reduced Cr(III) and Cr(VI), or chromate. Chromate, the most biologically active species, is readily taken up by living cells and reduced intracellularly, via reactive intermediates, to stable Cr(III) species. Cr(III), the most abundant form of chromium in the environment, does not readily cross cell membranes and is relatively inactive in vivo. However, intracellular Cr(III) can react slowly with both nucleic acids and proteins and can be genotoxic. We have investigated the genotoxicity of Cr(III) in vitro using a DNA replication assay and in vivo by CaCl2-mediated transfection of chromium-treated DNA into Escherichia coli. When DNA replication was measured on a Cr(III)-treated template using purified DNA polymerases (either bacterial or mammalian), both the rate of DNA replication and the amount of incorporation per polymerase binding event (processivity) were greatly increased relative to controls. When transfected into E. coli, Cr(III)-treated M13mp2 bacteriophage DNA showed a dose-dependent increase in mutation frequency. These results suggest that Cr(III) alters the interaction between the DNA template and the polymerase such that the binding strength of the DNA polymerase is increased and the fidelity of DNA replication is decreased. These interactions may contribute to the mutagenicity of chromium ions in vivo and suggest that Cr(III) can contribute to chromium-mediated carcinogenesis.