Recent advances in metal carcinogenicity

The carcinogenicity of nickel, chromium, arsenic,cobalt, and cadmium compou nds has long been recognized. Nevertheless, the mechanisms involved in tumo r formation are not well understood. The carcinogenic potential depends on metal species; major determinants are oxidation state and solubility. Two m odes of action seem to be predominant: the induction of oxidative DNA damag e and the interaction with DNA repair processes, leading to an enhancement of genotoxicity in combination with a variety of DNA-damaging agents. Nucle otide excision repair (NER) is inhibited at low, non-cytotoxic concentratio ns 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(I I) and magnesium(II). Potentially sensitive targets are so-called zinc fing er structures present in several DNA repair enzymes such as the mammalian X PA protein and the bacterial formamidopyrimidine-DNA glycosylase (Fpg prote in); 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 decrea sing the repair capacity towards DNA lesions induced by endogenous and exog enous mutagens, which may in turn increase the risk of tumor formation.