IN-VITRO DNA-DAMAGE AND MUTATIONS INDUCED BY A MACROCYCLIC TETRAAMIDECHROMIUM(V) COMPLEX - IMPLICATIONS FOR THE ROLE OF CR(V) PEPTIDE COMPLEXES IN CHROMIUM-INDUCED CANCERS

Electron paramagnetic resonance and electronic absorption spectroscopi es have shown that unlike the bidentate Cr(V) complex [Cr(ehba)2O]- (e hba = 2-hydroxy-2-ethylbutanoato(2)), I, the macrocyclic tetradentate complex, [Cr (mampa-dcb)(O)]- (mampa-dcb = -tetraoxo-2,2,9,9-tetrameth yl-12,12-diethyl-1,4,7, 10-tetraazacyclotridecane), II, is substitutio nally inert. Low levels of DNA strand cleavage were observed after tre atment with 11 under physiological conditions (50 mM sodium phosphate, pH 7.4, 37-degrees-C) at concentrations as high as 2 mM for periods a s long as 2 days. II also induces a lower number of revertants in muta tion assays with Salmonella typhimurium TA100 than I when identical Cr concentrations are applied. The slopes of the linear portion of the d ose - response curves are parallel, however, indicating that the mutag enicity 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, glutat hione. This indicates that ligand exchange with DNA and/or reduction t o Cr(IV) are not responsible for the mutagenicity of II (unlike I). It is believed that II reversibly but weakly intercalates with DNA placi ng the Cr(V) center in close proximity for hydrogen atom abstraction o r oxo-transfer reactions to ensue. This tetraamide complex is a good s tructural 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 mech anism by which Cr(VI) causes cancer.