Oxygen radical-mediated DNA damage by redox-active chromium(III) complexes

Abstract

The mechanism of DNA damage induced by Cr(III) complexes is currently unknown even though it is considered to be the ultimate biologically active oxidation state of chromium. In this study, we have employed the Salmonella reversion assay to identify mutagenic Cr(III) complexes. Cyclic voltammetry was used to differentiate the redox kinetics between mutagenic and selected nonmutagenic Cr(III) species. Plasmid relaxation of supercoiled DNA was employed to show in vitro interactions with plasmid DNA and correlate the interactions with the electrochemical behavior and biological activity. The results of this study demonstrate that the mutagenic Cr(III) complexes identified in the Salmonella reversion assay display characteristics of reversibility and positive shifts of the Cr(III)/Cr(II) redox couple consistent with the ability of these Cr(III) complexes to serve as cyclical electron donors in a Fenton-like reaction. These same mutagenic complexes display an ability to relax supercoiled DNA in vitro, presumably by the induction of single-strand breaks. Nonmutagenic complexes were selected to test different ligands to determine how the ligand directs the activity of Cr(III) complexes. All nonmutagenic complexes tested thus far have shown classical irreversibility, more negative reduction potentials, and an inability to relax supercoiled plasmid DNA. These results suggest that the mechanism by which chromium complexes potentiate mutagenesis involves an oxygen radical as an active intermediate. These data also demonstrate the effect of associated ligands with regard to the ability of a metal to generate an active redox center.

Recent advances in the nutritional biochemistry of trivalent chromium

“…Hence, these studies are consistent with investigations that demonstrated that mutagenic forms of trivalent Cr possessed chelating ligands containing pyridine-type N or other imine-N (e.g. 2,2k-bipyridine, phenanthroline and Schiff bases) coordinated to the metal and that they generated reactive oxygen species (Sugden et al 1992). Cr compounds that do not have imine ligands lack the DNA cleaving activity in the presence of biological reducing agents (Speetjens et al 1999b).…”

Oxidative mechanisms in the toxicity of metal ions

“…Sugden et al 73 have employed the Salmonella reversion assay to identify mutagenic Cr(III) complexes. Relaxation of supercoiled DNA was used to show in vitro interactions with plasmid DNA.…”

Mechanisms of the Carcinogenic Chromium(VI)-induced DNA-Protein Cross-linking and Their Characterization in Cultured Intact Human Cells

“…Hydroxyl radicals ( ⅐ OH), which are generated during the cellular reduction of chromate (25) are also capable of causing DNAprotein cross-linking (26,27) and are considered as the "ultimate agents" in chromate carcinogenesis (28). Cr(III) and the reactive intermediate states of chromium may also be considered as carcinogenic because ⅐ OH radicals are shown to be generated by redox cycling of Cr(III) (29), and DNA damage has been shown to be caused by intermediate valence states of chromium, such as Cr(V) (30).…”