Reductive activation with cysteine represents a chromium(III)-dependent pathway in the induction of genotoxicity by carcinogenic chromium(VI).

Abstract

Induction of DNA damage by carcinogenic hexavalent chromium compounds [Cr(VI)] results from its reduction to lower oxidation states. Reductive metabolism of Cr(VI) generates intermediate Cr(V/IV)species, organic radicals, and finally Cr(III), which forms stable complexes with many biological ligands, including DNA. To determine the biological significance of different reaction products, we examined genotoxic responses and the formation of DNA damage during reduction of Cr(VI) by its biological reducer, cysteine. We have found that cysteine-dependent activation of Cr(VI) led to the formation of Cr-DNA and cysteine-Cr-DNA adducts as well as interstrand DNA cross-links. The yield of binary and ternary DNA adducts was relatively constant at different concentrations of Cr(VI) and averaged approximately 54 and 45%, respectively. Interstrand DNA cross-links accounted on average for 1% of adducts, and their yield was even less significant at low Cr(VI) concentrations. Reduction of Cr(VI) in several commonly used buffers did not induce detectable damage to the sugar-phosphate backbone of DNA. Replication of Cr(VI)-modified plasmids in intact human fibroblasts has shown that cysteine-dependent metabolism of Cr(VI) resulted in the formation of mutagenic and replication-blocking DNA lesions. Selective elimination of Cr-DNA adducts from Cr(VI)-treated plasmids abolished all genotoxic responses, indicating that nonoxidative, Cr(III)-dependent reactions were responsible for the induction of both mutagenicity and replication blockage by Cr(VI). The demonstration of the mutagenic potential of Cr-DNA adducts suggests that these lesions can be explored in the development of specific and mechanistically important biomarkers of exposure to toxic forms of Cr.

In vivo genotoxic effects of industrial waste leachates in mice following oral exposure

“…Although epidemiological studies have not found a connection between chromium (VI) exposure and cancer incidence in residential populations, positive associations between chromium exposure and cancers of the digestive tract were reported among workers exposed to high levels of chromium (VI) [Proctor et al, 2002]. Several reports demonstrate that chromium (VI) is metabolized to a carcinogenic derivative by forming stable complexes with biological ligands like DNA [Zhitkovich et al, 2002], and systemic absorpEnvironmental and Molecular Mutagenesis. DOI 10.1002/em tion and increases in the rate of cancer have been observed in people chronically exposed above the permissible limits [IARC, 1990].…”

Mechanistic Insights from the NTP Studies of Chromium

“…Cr(III) has been shown to interact directly with DNA and other macromolecules to induce chromosomal alterations and mutational changes in DNA as a consequence of DNA adduct formation (Zhitkovich et al 2001(Zhitkovich et al , 2002Quievryn et al 2003;Reynolds et al 2007). Cr(III) forms both binary and ternary DNA adducts (O'Brien, Ceryak, and Patierno 2003;Zhitkovich 2005), with FIGURE 7.-Comparison of total chromium (Cr; mg Cr/g tissue) in red blood cells (RBCs), liver, kidney, and glandular stomach (GS) of male rats (left) and female mice (right) after 182 days of ingestion of similar time-weighted average daily doses of Cr(III) (resulting from exposure in feed to 2,000 ppm chromium picolinate monohydrate [CPM]) and Cr(VI) (resulting from exposure in drinking water to 516 mg sodium dichromate dihydrate (SDD)/L).…”

Liver Aspartate Transaminase Isoenzymes as Biomarkers of Chronic Exposure to Chromium(VI)

“…Hexavalent chromium is transported into the cell via non-specifi c anion transport systems (3,4), where it converts to trivalent chromium (Cr III ), whose highest levels have been reported in the kidney, liver, spleen, and bones (5). Although cytotoxic mechanisms are not exactly understood, several studies have showed that Cr VI induces oxidative stress, DNA damage, single-and double-strand breaks, and affects survival signalling pathways (6)(7)(8). This damage and molecular events are believed to be induced by free radicals (HO˚-and R˚) produced during chromium oxidation/reduction (9).…”