Possible Roles of Nitric Oxide and Redox Cell Signaling in Metal-Induced Toxicity and Carcinogenesis: A Review

Toxic doses of transition metals are capable of disturbing the natural oxidation/reduction balance in cells through various mechanisms stemming from their own complex redox reactions with endogenous oxidants and effects on cellular antioxidant systems. The resulting oxidative stress may damage redox-sensitive signaling molecules, such as NO, S-nitrosothiols, AP-1, NF-kappaB, IkappaB, p53, p21ras, and others, and thus derange the cell signaling and gene expression systems. This, in turn, may produce a variety of toxic effects, including carcinogenesis. Experimental support for the relevance of oxidative damage to the mechanisms of metal toxicity and carcinogenicity is particularly strong for two essential (but toxic when overdosed) metals–iron and copper– and three well-established human metal carcinogens–nickel, chromium, and cadmium. However, along with more specific effects of toxic metals associated with their selective binding to particular cell constituents and affecting calcium signaling, oxidative damage seems to become important as well in explaining mechanisms of pathogenicity of other metals, such as lead, mercury, and arsenic.

Buzard GS, Kasprzak KS. J Environ Pathol Toxicol Oncol. 2000; 19(3):179-99. 10983886 PubMed.

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