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 toexperimental animals. One frequently discussed mechanism involved in tumorformation is an increase in reactive oxygen species by both metals with thesubsequent generation of oxidative DNA damage. In the present study we usedhuman HeLa cells to investigate the potential of nickel(II) and cadmium(II)to induce DNA lesions typical for oxygen free radicals in intact cells andthe effect on their repair. As indicators of oxidative DNA damage, wedetermined the frequencies of DNA strand breaks and of lesions recognizedby the bacterial formamidopyrimidine-DNA glycosylase (Fpg protein),including 7,8- dihydro-8-oxoguanine (8-hydroxyguanine), a pre-mutagenic DNAbase modification. Nickel(II) caused a slight increase in DNA strand breaksat 250 microM and higher, while the frequency of Fpg-sensitive sites wasenhanced only at the cytotoxic concentration of 750 microM. The repair ofoxidative DNA lesions induced by visible light was reduced at 50 microM andat 100 microM nickel(II) for Fpg-sensitive sites and DNA strand breaks,respectively; the removal of both types of lesions was blocked nearlycompletely at 250 microM nickel(II). In the case of cadmium(II), DNA strandbreaks occurred at 10 microM and no Fpg- sensitive sites were detected.However, the repair of Fpg-sensitive DNA lesions induced by visible lightwas reduced at 0.5 microM cadmium(II) and higher, while the closure of DNAstrand breaks was not affected. Since oxidative DNA damage is continuouslyinduced during aerobic metabolism, an impaired repair of these lesionsmight well explain the carcinogenic action of nickel(II) and cadmium(II).