The carcinogenicity of nickel, chromium, arsenic, cobalt, and cadmium compounds has long been recognized. Nevertheless, the mechanisms involved in tumor formation are not well understood. The carcinogenic potential depends on metal species; major determinants are oxidation state and solubility. Two modes of action seem to be predominant: the induction of oxidative DNA damage and the interaction with DNA repair processes, leading to an enhancement of genotoxicity in combination with a variety of DNA-damaging agents. Nucleotide excision repair (NER) is inhibited at low, non-cytotoxic concentrations of nickel(II), cadmium(II), cobalt(II), and arsenic(III); the repair of oxidative DNA base modifications is disturbed by nickel(II) and cadmium(II). One reason for repair inhibition appears to be the displacement of zinc(II) and magnesium(II). Potentially sensitive targets are so-called zinc finger structures present in several DNA repair enzymes such as the mammalian XPA protein and the bacterial formamidopyrimidine-DNA glycosylase (Fpg protein); detailed studies revealed that each zinc finger protein exerts unique sensitivities toward toxic metal ions. Taken together, toxic metal ions may lower the genetic stability by inducing oxidative DNA damage and by decreasing the repair capacity towards DNA lesions induced by endogenous and exogenous mutagens, which may in turn increase the risk of tumor formation.
Congress of Toxicology in Developing Countries (4th CTOX-DC), 4th, Antalya, Turkey, 1999-11-06–1999-11-10
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