Peroxynitrite: A Biologically Significant Oxidant

doi:10.1016/S0306-3623(97)00418-7

General Pharmacology: The Vascular System

Volume 31, Issue 2, August 1998, Pages 179-186

General Pharmacology...

https://doi.org/10.1016/S0306-3623(97)00418-7 Get rights and content

Abstract

1.
Peroxynitrite is a short-lived and damaging oxidant that forms rapidly from the reaction of superoxide with nitric oxide.
2.
In 1990, Joseph Beckman proposed that peroxynitrite contributed significantly to pathological oxidative stress in living tissues, and subsequent evidence strongly supports this proposal.
3.
In this review, we outline the properties of peroxynitrite and discuss how it can affect biological systems and contribute to human pathologies.

Introduction

Our tissues are continually exposed to damaging reactive oxygen species (ROS) (Halliwell and Gutteridge, 1989). Defense mechanisms protect against or repair the nonspecific damage caused by these ROS (see end of article for list of abbreviations) and include enzymes such as the superoxide dismutases (SODs), glutathione peroxidases, and low molecular weight antioxidants such as vitamin C, vitamin E, and glutathione (Sies, 1993). Oxidative stress occurs when the production of damaging ROS overwhelms the antioxidant defenses (Halliwell and Gutteridge, 1989), and this arises in a range of human pathologies, including ischemia-reperfusion injury, inflammation, and neurodegenerative diseases (Ames et al., 1993).

The ROS superoxide (O₂^•−) is formed continually from normal biological reactions, such as the mitochondrial respiratory chain and NADPH oxidase in macrophages and neutrophils Baggiolini and Wymann 1990, Shigenaga et al. 1994. The ROS H₂O₂ arises directly from enzymes such as monoamine oxidase and from the dismutation of O₂^•− by SOD Ames et al. 1993, Chance et al. 1979. These ROS lead to oxidative damage, forming lipid peroxides, oxidized proteins, and damaged DNA in living tissues Ames et al. 1993, Halliwell and Gutteridge 1989. However, because neither O₂^•− nor H₂O₂ is sufficiently reactive, much of the oxidative damage found in vivo was ascribed to the extremely reactive hydroxyl radical (^•OH), formed from H₂O₂ by the metal-catalyzed Fenton reaction (Halliwell and Gutteridge, 1989). In the presence of O₂^•− and catalytic amounts of free iron or copper, this becomes the metal-catalyzed Haber-Weiss reaction (Halliwell and Gutteridge, 1989).

However, there are several difficulties with this hypothesis. For example, because ^•OH can only diffuse a few ångstroms before reacting, far greater concentrations of free metals and H₂O₂ than those present in vivo would be required to cause oxidative damage Beckman 1994, Crow and Beckman 1996. For this and many other reasons, ^•OH may not be as important a cause of oxidative stress in vivo as was thought in the past Beckman 1994, Crow and Beckman 1996.

In humans, nitric oxide (NO^•) is formed from arginine, O₂, and NADPH by nitric oxide synthases (NOSs) and is used as a diffusible messenger to regulate vascular tone, modulate neuronal signaling, and to kill pathogens (Bredt and Snyder, 1994). NO^• also reacts rapidly with O₂^•− to form the potent oxidant peroxynitrite (the term peroxynitrite refers to the sum of the peroxynitrite anion (ONOO⁻) and its conjugate acid peroxynitrous acid (ONOOH) (Blough and Zafiriou, 1985). This led Beckman to suggest (Beckman et al., 1990) that O₂^•− is more likely to cause oxidative damage in vivo by reacting with NO^• to form peroxynitrite, than by producing ^•OH (Beckman, 1994a,b; Crow and Beckman, 1996). In this review we describe the properties of peroxynitrite and discuss its contribution to oxidative stress in vivo. (There are a number of extensive reviews on peroxynitrite by the pioneers of this field (e.g., Beckman 1994, Beckman and Koppenol 1996, Beckman and Tsai 1994, Beckman et al. 1994a, Beckman et al. 1994b, Crow and Beckman 1996, Ischiropoulos et al. 1995, Koppenol et al. 1992, Pryor and Squadrito 1995).)

Section snippets

Formation and properties of peroxynitrite

Because both NO^• and O₂^•− are free radicals, they react together extremely rapidly at close to the diffusion limit to form peroxynitrite Blough and Zafiriou 1985, Goldstein and Czapski 1995, Huie and Padmaja 1993.

Peroxynitrite is not a free radical but is a short-lived and far more reactive species than its precursors (Beckman et al., 1990). Peroxynitrite reacts with and damages many important biological molecules including thiols, lipids, proteins, and nucleic acids by a number of mechanisms

Peroxynitrite formation in vivo

Because of their very rapid reaction together, whenever NO^• and O₂^•− are present simultaneously in vivo the damaging oxidant peroxynitrite may form. The extent of this reaction is determined by the steady state concentrations of NO^• and O₂^•−, which are set by their relative rates of formation and decomposition (Beckman and Tsai, 1994). O₂^•− is produced continually in vivo by the mitochondrial respiratory chain (Shigenaga et al., 1994) and NADPH oxidase (Baggiolini and Wymann, 1990). Even so,

Biological consequences of peroxynitrite formation

Peroxynitrite is significantly more reactive and damaging than its precursors and is therefore more toxic to cells than H₂O₂, O₂^•−, or NO^• Brunelli et al. 1995, Zhu et al. 1992. This toxicity arises from the damaging reactions of peroxynitrite and because it causes damage well away from its site of synthesis, due to its relatively long lifetime and ability to pass through lipid bilayers (Beckman et al., 1990). Therefore, intracellular peroxynitrite formation causes damage throughout that cell,

Experimental investigations using peroxynitrite

A first step is often to study the interaction of authentic peroxynitrite with biological material. For this a stable peroxynitrite stock solution is required. These are now available commercially (e.g., Upstate Biotechnology, Lake Placid, NY) but can be prepared easily and cheaply by most laboratories (Beckman et al., 1994a). The most usual way is by reacting acidified H₂O₂ with NaNO₂ in a flow reactor, followed rapidly by quenching in NaOH to stabilize the peroxynitrite (Beckman et al., 1994a)

Measurement of peroxynitrite formation

There are a number of approaches that can be used to measure peroxynitrite formation in biological systems. The oxidation of nonfluorescent dihydrorhodamine to its fluorescent product rhodamine 123 Ischiropoulos et al. 1995, Kooy et al. 1994 is relatively selective for peroxynitrite over O₂^•−, H₂O₂, or NO^• and has been used in isolated organelles, cells, and intact animals Packer and Murphy 1995, Packer et al. 1996a, Packer et al. 1996b, Szabo et al. 1995. However, considerable care must be

Summary

The pioneering work of Beckman and co-workers has led to fundamental new insights into the nature of oxidative stress, and peroxynitrite is now established as one of the major damaging oxidants produced in humans. In our view, the major question remaining is the proportion of oxidative damage in vivo that is due to peroxynitrite. Although it is tempting to ascribe most oxidative damage in vivo to peroxynitrite, we should be cautious: in the past O₂^•− and ^•OH have had this role.

Much remains to

Acknowledgements

Work in our laboratory is supported by grants to M. P. M. from the Health Research Council of New Zealand, the Neurological Foundation of New Zealand, and the Lottery Health Grants Committee. J. L. S. is grateful to the Neurological Foundation of New Zealand for the award of a Miller Scholarship. We thank Professor Christine Winterbourn, Dr. Iain Lamont, and Dr. Sally McCormick for their helpful comments on the manuscript.

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REVIEWPeroxynitrite: A Biologically Significant Oxidant

Abstract

Introduction

Section snippets

Formation and properties of peroxynitrite

Peroxynitrite formation in vivo

Biological consequences of peroxynitrite formation

Experimental investigations using peroxynitrite

Measurement of peroxynitrite formation

Summary

Acknowledgements

Arch. Biochem. Biophys.

Trends Biochem. Sci.

Biochem. Biophys. Res. Commun.

Arch. Biochem. Biophys.

Meth. Enzymol.

FEBS Lett.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Methods

Arch. Biochem. Biophys.

Anal. Biochem

J. Biol. Chem.

FEBS Lett.

Free Rad. Biol. Med.

Free Rad. Biol. Med.

FEBS Lett.

FEBS Lett.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

J. Biol. Chem.

FEBS Lett.

Eur. J. Pharmacol.

J. Biol. Chem.

Free Radical Biol. Med.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

Life Sci.

Food Chem. Toxicol.

FEBS Lett.

Biochem. Pharmacol.

FEBS Lett.

J. Biol. Chem.

Arch. Biochem. Biophys.

Free Radical Biol. Med.

J. Biol. Chem.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Arch. Biochem. Biophys.

Biochem. Pharmacol.

Biochim. Biophys. Acta.

Chem. Biol. Interact.

Biochem. Biophys. Res. Commun.

FEBS Lett.

Anal. Biochem.

Oxidants, antioxidants, and the degenerative diseases of aging

Proc. Natl. Acad. Sci. USA

Glutathione protects astrocytes from peroxynitrite-mediated mitochondrial damage

Dev. Neurosci

REVIEW
Peroxynitrite: A Biologically Significant Oxidant