© 1993 Oxford University Press
research-article |
In vitro DNA damage and mutations induced by a macrocyclic tetraamide chromium(V) complex: implications for the role of Cr(V) peptide complexes in chromium-induced cancers
Department of Inorganic Chemistry, University of Sydney NSW 2006
2Department of Genetic Toxicology Worksafe Australia, GPO Box 58, Sydney, NSW 2001
3Department of Research School of Chemistry, Australian National University Canberra, ACT 0200, Australia
4Department of Chemistry, Carnegie-Mellon University Pittsburgh, PA 15213, USA
1To whom correspondence should be addressed
Electron paramagnetic resonance and electronic absorption spectroscopies have shown that unlike the bidentate Cr(V) complex [Cr(ehba)2O]– (ehba = 2-hydroxy-2-ethylbutanoato(2—)), I, the macrocyclic tetradentate complex, [Cr (mampa-dcb)(O)]– (mampa-dcb = 5,6-(4,5-dichlorobenzo)-3,8,11,13-tetraoxo-2,2,9,9-tetramethyl-12,12-diethyl-1,4,7,10-tetraazacyclotridecane), II, is substitutionally inert. Low levels of DNA strand cleavage were observed after treatment with II under physiological conditions (50 mM sodium phosphate, pH 7.4, 37°C) at concentrations as high as 2 mM for periods as long as 2 days. II also induces a lower number of revertants in mutation assays with Salmonella typhimurium TA100 than I when identical Cr concentrations are applied. The slopes of the linear portion of the dose—response curves are parallel, however, indicating that the mutagenicity of II is comparable to I. II is stable toward ligand exchange, reduction and disproportionation in the mutagenicity test medium and also in the presence of bacteria and the common cell reductant, glutathione. This indicates that ligand exchange with DNA and/or reduction to Cr(IV) are not responsible for the mutagenicity of II (unlike I). It is believed that II reversibly but weakly intercalates with DNA placing the Cr(V) center in close proximity for hydrogen atom abstraction or oxo-transfer reactions to ensue. This tetraamide complex is a good structural and biomimetic model for non-sulfur-containing Cr(V) peptide species that may form in vivo from reactions of Cr(VI) with peptides. Hence, it is likely to be relevant to understanding one possible mechanism by which Cr(VI) causes cancer.