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Chem Res Toxicol. 2008 Nov;21(11):2188-94. doi: 10.1021/tx800265g.

Reduction with glutathione is a weakly mutagenic pathway in chromium(VI) metabolism.

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  • 1Department of Pathology and Laboratory Medicine, Brown University, 70 Ship Street, Providence, Rhode Island 02912, USA.

Abstract

Although reductive metabolism of Cr(VI) always results in the production of Cr(III) and extensive Cr-DNA binding, cellular studies have indicated that different reduction processes are not equivalent in the induction of mutagenic events. Here, we examined mutagenicity and formation of Cr-DNA damage by Cr(VI) activated in vitro by one of its important reducers, glutathione (GSH). Our main focus was on reactions containing 2 mM GSH, corresponding to its average concentration in CHO (1.8 mM) and V79 (2.6 mM) mutagenicity models. We found that Cr(VI) reduction by 2 mM GSH produced only weak mutagenic responses in pSP189 plasmids replicated in human fibroblasts. Reductive activation of Cr(VI) with 5 mM GSH resulted in approximately 4-times greater DNA adduct-normalized yield of mutations. Mutagenic DNA damage formed in GSH-chromate reactions was caused by nonoxidative mechanisms, as blocking of Cr-DNA adduction led to a complete loss of mutagenesis. All GSH-mediated reactions also lacked significant DNA single-strand breakage. We developed a sensitive HPLC procedure for the detection of GSH-Cr-DNA cross-links based on the dissociation of DNA-conjugated GSH by Cr(III) chelation and its derivatization with monobromobimane. Weak mutagenicity of 2 mM GSH reactions was associated with a low production of mutagenic GSH-Cr-DNA cross-links (5.0% of total Cr-DNA adducts). In agreement with their greater mutation-inducing ability, 5 mM GSH reactions generated 4-5 times higher levels of GSH-DNA cross-linking. Overall, our results indicate that chromate reduction by physiological concentrations of GSH is a weakly mutagenic process, which is consistent with low mutagenicity of Cr(VI) in ascorbate-deficient cells.

PMID:
18808157
[PubMed - indexed for MEDLINE]
PMCID:
PMC2665875
Free PMC Article
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