Characterization of Nonmutagenic Cr(III)−DNA Interactions

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Abstract
Exposure of cells or animals to carcinogenic chromium(VI) (Cr(VI)) produces Cr(III)−DNA adducts. The relevance of these lesions to Cr(VI)-induced tumors is unclear. Various Cr(III) complexes have been used to model the products resulting from Cr(VI) metabolism in order to gain mechanistic insights. The purpose of this study was to characterize interactions of Cr(III) complexes with DNA in order to evaluate their use as models for these purposes. The reactivity of DNA with chromic chloride hexahydrate (CrCl3) and sodium bis(l-cysteinato)chromium(III) dihydrate (Cr(cys)2-) was compared to that with cis-diamminedichloroplatinum(II) (cis-platin). Both Cr(III) and Pt(II) cause unwinding of supercoiled DNA that can be visualized as a mobility shift by gel electrophoresis. Chromic chloride was much less distorting than cis-platin, unwinding DNA by only 1−2°, and Cr(cys)2- interacted with DNA only weakly. Consistent with in vitro studies, CrCl3 produced Cr−DNA adducts in CHO AA8 cells at levels equivalent to those obtained with Cr(VI), whereas Cr(cys)2- did not produce significant adducts. Lesions produced by CrCl3 were not mutagenic in the hypoxanthine−Gua−phosphoribosyl−transferase assay. These data are consistent with CrCl3 producing a nondistorting lesion, perhaps by association with the phosphate backbone. There are two possible interpretations of these results: Either the Cr(III) products formed by Cr(VI) metabolism are not modeled by CrCl3 and Cr(cys)2- complexes, or Cr(III) is not an active species for Cr(VI)-induced DNA damage. This study provides the first structural evidence for Cr(III)−DNA adducts. A molecular understanding of Cr(III)−DNA interactions will be necessary before we can determine their relevance in Cr(VI)-induced cancers.