JULY/AUGUST 1996 VOLUME 9, NUMBER 5 © Copyright 1996 by the American Chemical Society
Commentary Nitric Oxide: Chemical Events in Toxicity It has been nearly ten years since the identification of nitric oxide as Endothelium-Derived Relaxing Factor (1). Simultaneous with this finding was the discovery that NO is a precursor to nitrate and to a nitrosating agent capable of converting ingested amines to nitrosamines (2). Thus, from the very beginning of research on NO, its schizophrenic properties have been apparent. NO is both an essential mediator of intercellular communication and a molecule that plays a role in tissue damage and carcinogenesis. The first review of the role of NO in N-nitrosation reactions was published in 1988 in the first volume of Chemical Research in Toxicology (3). In the intervening years, a tremendous amount of work has been published on the involvement of NO in damage to membranes, nucleic acid, proteins, and ultimately cells. How can one diatomic molecule exert so many distinct biological effects? At the heart of the answer to this question is the fact that NO has an unpaired electron which enables it to couple to metals, oxygen, superoxide, and other free radicals. The products of these coupling reactions are capable of exerting their own deleterious effects. Therefore, NO directly damages cellular constituents and is the precursor to a series of toxic derivatives. The extent to which NO or one of its progeny participate in a given reaction depends upon the relative concentrations of the various reagents and the rate coefficients for the competing reactions. The importance of understanding the balance of the various reactions of NO has probably done more to generate interest in kinetics than two generations of graduate level textbooks. This year’s forum in Chemical Research in Toxicology is devoted to exploring the range of reactions involving NO that are related to toxicological events. Rubbo, Darley-Usmar, and Freeman begin the forum with an overview of the involvement of NO in tissue free radical injury. This article focuses on some of the chemical S0893-228x(96)00475-4 CCC: $12.00
events that are essential for understanding NO biochemistry and identifies some of the biologically important targets. The authors provide a balanced approach to the literature and highlight reactions where NO protects against tissue injury as well as reactions where it contributes to tissue injury. This presentation is followed by an article by Tamir, Burney, and Tannenbaum describing the reactions of NO that give rise to DNA damage. As expected, there are multiple ways by which NO can damage DNA. It can be converted to a nitrosating agent that deaminates nucleic acid bases or it can trigger oxidative chemistry leading to base or sugar oxidation. The latter can result in strand scission. NO also reacts with proteins, in particular, with the metal atoms of metalloproteins. This may be one of the mechanisms by which macrophages defend against invading pathogens. Radi highlights the reactions of NO with a variety of metal centers in proteins and ties this to the mechanisms of cell killing. A great deal of excitement has been generated by the realization that NO couples to the superoxide anion to generate peroxynitrite (4). Peroxynitrite is a potent oxidant that appears to account for some of the toxic effects of NO. The last two articles in the forum are devoted to the chemistry of peroxynitrite. Beckman reviews the generation of peroxynitrite, its chemical properties, and its reaction with protein residues, especially tyrosine. Tyrosine nitration provides a useful biomarker that has been used to implicate peroxynitrite in a variety of toxicological processes including the genesis of neurological diseases. Competitive with peroxynitrite reaction with cellular constituents is its addition to CO2 to form a putative nitrosoperoxycarbonate. The rate coefficient for this reaction predicts that it should consume all the peroxynitrite generated in the presence of physiological concentrations of bicarbonate. Does this represent a protective mechanism for the © 1996 American Chemical Society
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consumption of peroxynitrite or does the peroxycarbonate constitute a novel oxidant with complementary chemistry to that of peroxynitrite? These questions are explored in an article by Lymar and Hurst that concludes the forum by reminding us that just when we think we have learned everything about NO, someone discovers a whole new branch of its chemistry. Life isn’t simple no matter how much we would like it to be. Rather than bemoan this fact, we should celebrate it because complexity provides continuing opportunites for research and improvements in human health. This is amply illustrated by the breadth of chemistry displayed by the simple diatomic molecule that is the subject of this year’s forum. We hope you’ll enjoy the stimulating contributions from each of our authors and that you will take away some new ideas of how NO may be related to your work.
Marnett
References (1) Palmer, R. M. J., Ferrige, A. G., and Moncada, S. (1987) Nitric oxide release accounts for the biological activity of endotheliumderived relaxing factor. Nature 327, 524-526. (2) Miwa, M., Stuehr, D. J., Marletta, M. A., and Tannebaum, S. R. (1987) Nitrosation of amines by stimulated macrophages. Carcinogenesis 8, 955-958. (3) Marletta, M. A. (1988) Mammalian synthesis of nitrite, nitrate, nitric oxide, and N-nitrosating agents. Chem. Res. Toxicol. 1, 249257. (4) Radi, R., Beckman, J. S., Bush, K. M., and Freeman, B. A. (1991) Peroxynitrite-induced membrane lipid peroxidation: The cytotoxic potential of superoxide and nitric oxide. Arch. Biochem. Biophys. 288, 481-487.
Lawrence J. Marnett Editor TX960475X
