Permeability, cytotoxicity, and genotoxicity of chromium (V) and chromium (VI) complexes in V79 Chinese hamster lung cells.

The genotoxicity of Cr(V) complexes in mammalian cells (V79 Chinese hamster lung cells) has been studied for the first time using the in vitro micronucleus assay. Two complexes were investigated, [CrO(ehba)2]-, which undergoes ligand-exchange and disproportionation reactions in the cell growth medium, and [CrO(mampa)]-, which is chemically inert in the medium for the duration of the exposure period. Results of in vitro micronucleus assays show that both complexes are genotoxic and exhibit similar potencies to that of [Cr2O7]2-. The permeabilities of the Cr(V) complexes were also investigated for the first time using particle-induced X-ray emission (PIXE) analysis of individual cells. The Cr uptake increased in the order: [Cr(phen)2-(H2O)2]3+ < [CrO(ehba)2]- < [CrO(mampa)]- < [Cr2O7]2-. Clonal assays showed that Cr(VI) exhibits an expectedly higher cytotoxicity than the Cr(V) complexes. While the genotoxicities of the Cr(V) and Cr(VI) complexes increase according to their permeabilities, the genotoxicities of the Cr(V) complexes are equal to, if not greater than, that of Cr(VI) in terms of the amount of Cr entering the cell. This supports other evidence that Cr(V), produced as a metabolic intermediate from the intracellular reduction of Cr(VI), may be important in Cr-induced cancers.

Microprobe X-ray absorption spectroscopic determination of the oxidation state of intracellular chromium following exposure of V79 Chinese hamster lung cells to genotoxic chromium complexes.

The oxidation state of intracellular chromium has been determined directly in mammalian lung cells exposed to mutagenic and carcinogenic chromium compounds. Microprobe X-ray absorption spectroscopy (XAS) experiments on single V79 Chinese hamster lung cells showed that Cr(VI) and Cr(V) complexes were reduced completely (>90%) to Cr(III) within 4 h of exposure of the cells. This result provides direct evidence for the hypothesis that these genotoxic oxidants react rapidly with intracellular reductants.

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.

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-tetrameth yl-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 degrees 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 ensure. 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.