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Chemical biology of nitric oxide: insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide

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Abstract

There has been confusion as to what role(s) nitric oxide (NO) has in different physiological and pathophysiological mechanisms. Some studies imply that NO has cytotoxic properties and is the genesis of numerous diseases and degenerative states, whereas other reports suggest that NO prevents injurious conditions from developing and promotes events which return tissue to homeostasis. The primary determinant(s) of how NO affects biological systems centers on its chemistry. The chemistry of NO in biological systems is extensive and complex. To simplify this discussion, we have formulated the “chemical biology of NO” to describe the pertinent chemical reactions under specific biological conditions. The chemical biology of NO is divided into two major categories, direct and indirect. Direct effects are defined as those reactions fast enough to occur between NO and specific biological molecules. Indirect effects do not involve NO, but rather are mediated by reactive nitrogen oxide species (RNOS) formed from the reaction of NO either with oxygen or superoxide. RNOS formed from NO can mediate either nitrosative or oxidative stress. This report discusses various aspects of the chemical biology of NO relating to biological molecules such as guanylate cyclase, cytochrome P450, nitric oxide synthase, catalase, and DNA and explores the potential roles of NO in different biological events. Also, the implications of different chemical reactions of NO with cellular processes such as mitochondrial respiration, metal homeostasis, and lipid metabolism are discussed. Finally, a discussion of the chemical biology of NO in different cytotoxic mechanisms is presented.

Introduction

The discovery of the endogenous formation of nitric oxide (NO) led to an explosion in research centering on the question, “what role(s) does this free radical molecule play in various biologic events?” Surprisingly, this diatomic free radical has been shown to be involved in numerous regulatory functions ranging from altering the cardiovascular system to modulating neuronal function (Fig. 1).1, 2, 3 In addition, NO has been shown to be part of the oxidative war chest of the immune system by virtue of involvement in anti-tumor and anti-pathogen host response (Fig. 1).4, 5 Though these functions of NO are beneficial in maintaining proper physiological homeostasis, NO also has been found to be involved in a number of different diseases, as well as inflammatory conditions that can ultimately lead to tissue injury. NO has been shown to participate in a large number of pathophysiological conditions such as arthritis, atherosclerosis, cancer, diabetes, numerous degenerative neuronal diseases, stroke, and myocardial infarction to name a few (Fig. 1).3, 6 However, there is considerable debate as to the exact function of NO in such diverse pathophysiological states. Though NO and NO-derived chemical species can inhibit enzyme function, alter DNA, and induce lipid peroxidation, NO has antioxidant properties, and the ability to protect cells against cytokine induced injury and apoptosis (see discussion below).

The confusion concerning NO’s involvement in tissue injury is further complicated by its multifaceted and often paradoxical action in various cytotoxic mechanisms. NO itself is not a powerful cytotoxic agent; however, it can render cells susceptible to other cytotoxic agents such as heavy metals, alkylating agents, and radiation (see discussion below). Yet, NO has been shown to be protective against an array of agents that induce oxidative stress, such as hydrogen peroxide (H2O2), alkyl hydroperoxides, and superoxide (see discussion below). NO reacts with some redox metal complexes, yet its reactivity varies from complex to complex (discussed within references 7 and 8). NO reacts with other radicals such as superoxide and lipid-derived radicals to form products such as ONOO and LOONO, which can further react with other biological targets to influence different physiological and cellular functions. NO can react with oxygen to form a variety of different reactive intermediates that are normally associated with smog and cigarette smoke. These chemical species can alter critical biomolecules such as enzymes and DNA.9 However, NO can also neutralize oxidants associated with oxidative stress and abate reactive oxygen species (ROS)-mediated toxicity.10

Quite understandably, the labyrinth of divergent behaviors exhibited by NO has lead to confusion. Indeed, NO researchers have voiced the following: “Is NO good or bad?” or “Can NO be both good and bad?” It is our impression that the answers to these questions are dictated by the unique chemistry of NO in biological systems. Where, when, and how much NO is present or is being produced under a given circumstance determines the biological response. To provide a guide through the diverse reactions NO mediates on biological systems, this review will focus on a discussion of the chemical biology of NO.7, 8, 11 The chemical biology of NO provides a framework of relevant chemical reactions and provides a perspective that hopefully will allow insight into understanding that the function(s) of NO depends on the specific biology being investigated.

Section snippets

Chemical biology of NO

Figure 2 illustrates two distinct categories of the chemical biology of NO; direct and indirect effects.7, 8, 11 Direct effects are those reactions in which NO interacts directly with biological molecules. In contrast, indirect effects are derived from the reaction of NO with either superoxide or oxygen, which yields reactive nitrogen oxide species (RNOS) (Fig. 2).7, 8, 11 The direct and indirect effects of NO reactions can also be separated based on the local concentration of NO produced

Direct effects of NO

The important NO reactions in biology are those whose rates are fast enough to be considered physiologically relevant. NO does not rapidly react with thiols or amines; however, the reaction of NO with some metal complexes and other free radicals are facile enough to be biologically relevant.

Indirect effects

Unlike direct effects, indirect effects are mediated by RNOS derived from either the NO/O2 or NO/O2 reaction (Fig. 8). Though some reports imply that NO reacts with diamagnetic species such as thiols or other bioorganic molecules, these reactions are far too slow to be significant in biological systems.76, 77 Therefore, reactions with thiols and amines have to first proceed through an activation step of NO by molecules such as oxygen or superoxide. The chemistry of the NO/O2 or NO/O2

Direct and indirect effects on examples of cellular metabolism

For the most part, we have discussed the influences of NO on cellular processes as either being direct or indirect. In each case, an illustration of the biological effect was described. However, NO can influence some cellular functions by both mechanisms. Whether direct effects or indirect effects are present can have profound influence on the biological outcome. For example, the presence of NO can inhibit P450 by either direct or indirect effects. Inhibition of cytochrome P450 by direct

Cytotoxic versus protective mechanisms of NO

Up to this point, we have been discussing individual effects of NO on specific cellular processes. However, NO has the reputation of not only being injurious but also protective. Nitric oxide can induce cytotoxicity in different cells as well as increase the toxicity of different agents, yet, NO can also be protective against oxidative stress. Whether NO is protective or cytotoxic depends on specific conditions.

Conclusion

Though NO may have numerous potential reactions, we have tried to provide a template to understand most of the reactions in terms of concentrations and timing. Differentiating the different chemical reactions in such a manner may help to evaluate their participation in vivo. Separation of direct effects and indirect effects can help in defining mechanisms as well to provide insights in devising potential strategies of treatment for different diseases.87, 148

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    Dr. David A. Wink received his Ph.D. in Chemistry at the University of California, Santa Barbara. Following a postdoctoral fellowship as a National Research Service Award recipient at the Massachusetts Institute of Technology in Biochemistry, he joined the Laboratory of Comparative Carcinogenesis at NCI-FCRDC as a Staff Fellow. He then joined the Radiation Biology Branch at NCI in 1995, where today he holds the position of Tenure Track Investigator.

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    Dr. James B. Mitchell received his Ph.D. from Colorado State University in Cellular Radiation Biology in 1978. He came to the NIH and the Radiation Oncology Branch of the NCI in 1979, and became an Independent Investigator in 1984. He served as Chief of the Radiobiology Section and later as Deputy Branch Chief of the Radiation Oncology Branch. In 1993, he was named Branch Chief of the Radiation Biology Branch.

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