Induction and repair inhibition of oxidative DNA damage by nickel(II) and cadmium(II) in mammalian cells.
Compounds of nickel(II) and cadmium(II) are carcinogenic to humans and to experimental animals. One frequently discussed mechanism involved in tumor formation is an increase in reactive oxygen species by both metals with the subsequent generation of oxidative DNA damage. In the present study we used human HeLa cells to investigate the potential of nickel(II) and cadmium(II) to induce DNA lesions typical for oxygen free radicals in intact cells and the effect on their repair. As indicators of oxidative DNA damage, we determined the frequencies of DNA strand breaks and of lesions recognized by the bacterial formamidopyrimidine-DNA glycosylase (Fpg protein), including 7,8-dihydro-8-oxoguanine (8-hydroxyguanine), a pre-mutagenic DNA base modification. Nickel(II) caused a slight increase in DNA strand breaks at 250 microM and higher, while the frequency of Fpg-sensitive sites was enhanced only at the cytotoxic concentration of 750 microM. The repair of oxidative DNA lesions induced by visible light was reduced at 50 microM and at 100 microM nickel(II) for Fpg-sensitive sites and DNA strand breaks, respectively; the removal of both types of lesions was blocked nearly completely at 250 microM nickel(II). In the case of cadmium(II), DNA strand breaks occurred at 10 microM and no Fpg-sensitive sites were detected. However, the repair of Fpg-sensitive DNA lesions induced by visible light was reduced at 0.5 microM cadmium(II) and higher, while the closure of DNA strand breaks was not affected. Since oxidative DNA damage is continuously induced during aerobic metabolism, an impaired repair of these lesions might well explain the carcinogenic action of nickel(II) and cadmium(II).
Dally
H
H
University of Bremen, Department of Biology and Chemistry, Germany.
Hartwig
A
A
D002104:Cadmium / Q000633:toxicity*; D002413:Cations, Divalent; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D009532:Nickel / Q000633:toxicity*; D016877:Oxidants / Q000633:toxicity*; D010084:Oxidation-Reduction
D002413:Cations, Divalent; D016877:Oxidants; D002104:Cadmium; D009532:Nickel