Importance of chromium-DNA adducts in mutagenicity and toxicity of chromium(VI)

Intracellular reduction of Cr(VI) results in the extensive formation of Cr-DNA adducts, among which Cr(III)-mediated DNA cross-links of glutathione, cysteine, histidine, and ascorbate represent a major class of DNA modifications. Cysteine-Cr(III)-DNA and glutathione-Cr(III)-DNA cross-links are the two most abundant lesions that collectively account for about 80% of all ternary Cr-DNA adducts in cultured cells. In vitro reduction of Cr(VI) also generates binary Cr(III)-DNA adducts, but their significant production in cells is uncertain. All ternary and a major fraction of binary Cr(III)-DNA adducts are formed by attack of DNA by Cr(III) complexes. The formation mechanisms for the relatively rare DNA-protein and interstrand DNA crosslinks have not yet been determined. All ternary Cr-DNA adducts were mutagenic during replication in human cells. The mutagenic and genotoxic potentials of Cr-DNA adducts were related to the bulkiness of the attached ligand, with large glutathione- and ascorbate-Cr(III)-DNA cross-links generating the highest yields of mutants. Cr-DNA adducts were responsible for all mutagenic and replication-blocking damage generated during reduction of Cr(VI) with cysteine or ascorbate, which are two main reducers of Cr(VI) in vivo. Nucleotide excision repair has been identified as the principal mechanism for removal of Cr-DNA adducts in human cells. The strong genotoxic potential of all main adducts and hypersensitivity of nucleotide excision repair deficient human cells to apoptosis and clonogenic death indicate that Cr-DNA adducts are also a significant cause of Cr(VI) toxicity. Thus, it appears that Cr-DNA adducts are key genetic lesions contributing to the induction of the main biological effects of Cr(VI), such as mutagenesis, replication inhibition, and cell death (Figure 6). The formation of genotoxic ternary Cr-DNA adducts is predicted to be independent of the reducing capacity of the cell and should exhibit linear dose dependence with respect to intracellular Cr(VI).