Reassessing the Significance of Chromium-DNA Adducts in Chromate Carcinogenicity

Chromium(VI) is a carcinogen and mutagen, and its mechanism of action is proposed to involve binding of its reduction product, chromium(III), to DNA. The two proposed products, binary and ternary adducts. Binary adducts are believed to be non-mutagenic, while ternary adducts are proposed to be pre-mutagenic and carcinogenic. This laboratory has shown that small oligonucleotide duplexes of DNA can be used to generate binary adducts of Cr(III). The structure of the Cr(III) binding site(s) on the duplex DNA can be established using a combination of paramagnetic NMR, EPR, and FTIR spectroscopies. Ternary adducts have never been directly observed; their existence has been inferred from studies measuring the Cr content and/or ligand content of DNA or from down screen assays. The extension of the experiments to generate and characterize binary adducts to the generation of ternary small molecule/peptide-Cr(III)-DNA adducts have failed to produce ternary adducts, as clearly shown by spectroscopic studies. Unsuccessful efforts to synthesis ternary adducts have included the addition of Cr(III) complexes, Cr(V) complexes, and Cr(VI) complexes and reducing agents to DNA. Based on hindsight, the generation of such adducts is actually unlikely; thus, while adducts between DNA and small molecules, peptides, and proteins may form during the reduction of chromate in vivo, Cr(III) does not appear to serve as the linkage.