Forming a chromium-based interstrand DNA crosslink: Implications for carcinogenicity.

The reduction of the carcinogen chromate has been proposed to lead to three Cr(III)-containing DNA lesions: binary adducts (Cr(III) and DNA), interstrand crosslinks, and ternary adducts (Cr(III) linking DNA to a small molecule or protein). Although the structures of binary adducts have recently been elucidated, the structures of interstrand crosslinks and ternary adducts are not known. Analysis of Cr(III) binding to an oligonucleotide duplex containing a 5'-CG site allows elucidation of the structure of an oxide- or hydroxide-bridged binuclear Cr(III) assembly bridging the two strands of DNA. One Cr(III) is directly coordinated by the N-7 atom of a guanine residue, and the complex straddles the helix to form a hydrogen bond between another guanine residue and a Cr(III)-bound aquo ligand. No involvement of the phosphate backbone was observed. The properties and stability of this Cr-O(H)-Cr-bridged complex differ significantly from those reported for Cr-induced interstrand crosslinks, suggesting that interstrand crosslinks resulting from chromate reduction may be organic in nature.

Examining the Potential Formation of Ternary Chromium-Histidine-DNA Complexes and Implications for Their Carcinogenicity.

The mutagenic and carcinogenic properties of chromium(VI) complexes have been ascribed to the formation of ternary Cr(III)-small molecule-DNA complexes. As part of these laboratories efforts to establish the structure and properties of discrete binary and ternary adducts of Cr(III) and DNA at a molecular level, the properties of Cr(III)-histidine-DNA complexes formed from Cr(III) were examined. These studies determined the composition of previously described "prereacted" chromium histidinate and reveal the reaction of "prereacted" chromium histidinate with DNA does not form ternary complexes as previously proposed. The products instead are chromium histidinate complexes weakly bound, probably in the minor groove, to DNA. These weakly bound adducts cannot be responsible for the mutagenic and carcinogenic properties ascribed to ternary Cr(III)-histidine-DNA adducts. The results of biological studies where "ternary adducts" of Cr(III), histidine, and DNA were made from "prereacted" chromium histidinate must, therefore, be interpreted with caution.

Molecular Structure of Binary Chromium(III)-DNA Adducts.

Chromium(VI) is a carcinogen and mutagen, and its mechanisms of action are proposed to involve binding of its reduction product, chromium(III), to DNA. The manner in which chromium(III) binds DNA has not been established, particularly at a molecular level. Analysis of oligonucleotide duplex DNAs by NMR, EPR, and IR spectroscopies in the presence of chromium(III) allows the elucidation of the Cr binding site. The metal centers were found to interact exclusively with guanine N7 positions. No evidence of chromium interactions with other bases or backbone phosphates nor of Cr forming intra-strand crosslinks between neighboring guanine residues was observed.