NOVEMBER/DECEMBER 1991 VOLUME 4, NUMBER 6 @Copyright 1991 by the American Chemical Society
Commentary The Role of Oxidative Damage in Metal Carcinogenicity Unraveling the mechanisms by which metals exert toxic or carcinogenic effects is one of the most interesting and challenging problems in contemporary toxicology. Metals and metal complexes, in many different physical forms, are widely distributed in the industrial environment and are major components of numerous hazardous waste sites. Some of these agents are carcinogenic in animals and probably in humans. Thus, there is considerable reason to study the molecular basis of their biological effects. A t first glance, the paradigms established for organic carcinogens would appear to provide insight into the mechanism of action of metals. Most activated metabolites of organic carcinogens are electrophiles that bind covalently to DNA and protein; likewise, transition metals exhibit a rich coordination chemistry with a variety of nucleophiles, including nucleic acid bases. In fact, coordination of certain platinum complexes to N-7 of purine residues in DNA appears to account for their antitumor activity. However, metals also exhibit complex redox chemistry, and there is ample precedent for the involvement of oxidation reactions in carcinogenesis. It is the possible involvement of oxidation-reduction processes in metal carcinogenesis that is the focus of this year's Forum. Klein, Frenkel, and Costa begin the Forum with an overview of the emerging evidence in support of a role for oxidation in metal carcinogenesis. Reactions are described by which metals such as chromium and nickel generate oxidants in living cells. The reaction of these oxidants with DNA is reviewed as well as the evidence that metals induce oxidative DNA damage. A unique property of metal carcinogens is their ability to act as inflammatory agents at the site of administration by forming insoluble particles that are targets for activated neutrophils. The inertness of the metal particles leads to "frustrated phagocytosis" that results in the generation of copious amounts of superoxide anion and hydrogen peroxide. The latter serves as a moderately stable prooxidant that enters adjacent cells and diffuses to DNA. There, it encounters bound metals and generates hydroxyl radical-like oxidants.
Thus, even redox-inactive metals have the potential to form radical oxidants as a result of their physical state. Kasprzak expands on the theme of metal-mediated DNA damage. He describes experiments linking metal redox chemistry to the mutational activation of oncogenes such as rus. Oxidation of DNA bases is known to trigger a range of mutations, but a complete catalog of mutations arising from specific products does not exist. Thus, it is not yet possible to link all mutations induced by metals to a particular product of oxidative damage. This is one of many areas identified in this Forum article that require additional experimental work. Standeven and Wetterhahn acknowledge that metaldependent oxidations lead to DNA damage in vitro, but they call attention to the scarcity of data demonstrating similar reactions in vivo. In fact, the results of initial attempts to detect oxidative damage in target organs for metal carcinogenesis appear unimpressive. Furthermore, these authors highlight a number of deficiencies in our understanding of the basic biochemistry required for metal carcinogenesis. For example, reduction of high valence states of chromium appears essential for its cellular uptake and redox activation, but the identity of the reducing agent(s) responsible has not been unequivocally established. Some likely possibilities are considered. By perusing these contributions, even the casual reader should come away with an accurate impression of the frontier of research on metal carcinogenesis. Literature data are critically evaluated and numerous suggestions are made for experimental exploration. Although most of the emphasis is on DNA modification, all of the authors acknowledge the possible importance of protein or membrane oxidation. The complexity of metal chemistry in biology is a source of both frustration and excitement. The smorgisbord of possibilities by which metals may transform cells promises to provide new concepts regarding the molecular events that lead to cancer. Lawrence J. Marnett Editor
0 1991 American Chemical Society
