Possible role of oxidative damage in metal-induced carcinogenesis.
This review presents and evaluates evidence relevant to the mechanisms of metal carcinogenicity with special emphasis on the emerging hypothesis of the oxidative nature of metals' effect on DNA. The carcinogenic transition metals are capable of in vivo binding with the cell nucleus and causing promutagenic damage that includes DNA base modifications, inter- and intramolecular crosslinking of DNA and proteins, DNA strand breaks, rearrangements, and depurination. The chemistry of that damage and the resulting mutations observed in vitro and in metal-induced tumors are both characteristic for oxidative attack on DNA. The underlying mechanism involves various kinds of active oxygen and other radical species arising from metal-catalyzed redox reactions of O2, H2O2, lipid peroxides, and others, with certain amino acids, peptides, and proteins. Other metal-mediated pathogenic effects, such as enhancement of lipid peroxidation, stimulation of inflammation, inhibition of cellular antioxidant defenses, and inhibition of DNA repair, may also contribute to that mechanism. Thus far, published data revealing the oxidative character of metal-induced promutagenic DNA alterations are particularly strong for two of the most powerful human metal carcinogens, chromium and nickel. However, without excluding contribution of other effects, the promotion of oxidative damage tends to take the leading role in explaining mechanisms of carcinogenicity and acute toxicity of certain other metals as well.
Kasprzak
K S
KS
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland 21702, USA.
D000818:Animals; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008670:Metals / Q000378:metabolism / Q000633:toxicity*; D016296:Mutagenesis / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000633:toxicity*
D002273:Carcinogens; D004785:Environmental Pollutants; D008670:Metals; D017382:Reactive Oxygen Species; D004247:DNA; D010100:Oxygen