Induction of mutagenic DNA damage by chromium (VI) and glutathione.
Certain chromium (Cr) compounds are known to be carcinogenic in humans and mutagenic in cell culture. However, the mechanism of Cr mutagenesis is not well understood. It appears that intracellular reduction of Cr by agents such as glutathione plays a role in the induction of DNA damage. We have used a simian virus 40-based shuttle vector to investigate the relationship between chromium-induced DNA damage and Cr mutagenicity. The treatment of the plasmid pZ189 with Cr(VI) plus glutathione (GSH) induced DNA strand breaks and reduced the plasmid biological activity, whereas Cr(III) treatment with or without GSH did not give rise to such DNA damage. When Cr(VI)/GSH- or Cr(III)/GSH-treated pZ189 was replicated in mammalian cells, a dose-dependent increase in mutant frequency was observed with Cr(VI)/GSH-treated pZ189, but not with Cr(III)/GSH-treated plasmid. About 43% of the mutants from Cr(VI)/GSH-treated pZ189 were deletion mutants. The remainder were base substitution mutants, mostly GC-->AT transitions and GC-->TA transversions. This pattern of mutagenesis is similar to that observed with other agents that cause oxidative DNA damage such as ionizing radiation and H2O2. These results support the hypothesis that Cr mutagenesis can be induced by the generation of reactive oxygen intermediates during the reduction of Cr(VI) by glutathione.
Liu
S
S
Department of Environmental Health, University of Cincinnati College of Medicine, Ohio 45267-0056, USA.
Dixon
K
K
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017608:Chromium Compounds / Q000378:metabolism / Q000633:toxicity*; D004249:DNA Damage; D016153:Genes, Suppressor; D005822:Genetic Vectors / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism / Q000633:toxicity*; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000187:drug effects; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D010084:Oxidation-Reduction; D012343:RNA, Transfer / Q000187:drug effects / Q000235:genetics; D017382:Reactive Oxygen Species; D014162:Transfection
D017608:Chromium Compounds; D009153:Mutagens; D017382:Reactive Oxygen Species; C096275:supF tRNA; D012343:RNA, Transfer; D005978:Glutathione