Physiology in medicine
The evolution of free radicals and oxidative stress

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Abstract

The superoxide free radical has come to occupy an amazingly central role in a wide variety of diseases. Our metabolic focus on aerobic energy metabolism in all cell types, coupled with some chemical peculiarities of the oxygen molecule itself, contribute to the phenomenon. Superoxide is not, as we once thought, just a toxic but unavoidable byproduct of oxygen metabolism. Rather it appears to be a carefully regulated metabolite capable of signaling and communicating important information to the cell’s genetic machinery. Redox regulation of gene expression by superoxide and other related oxidants and antioxidants is beginning to unfold as a vital mechanism in health and disease.

Section snippets

A redox primer

At the risk of inducing unpleasant flashbacks to college chemistry courses, let us consider the class of chemical reactions upon which our bodies rely for energy production. Reduction-oxidation (or redox) reactions are at the core of our metabolic machinery. Redox reactions involve the transfer of electrons or hydrogen atoms from one reactant to another. (The process of taking away electrons is called “oxidation,” because oxygen does it so well. The substance receiving electrons becomes

Oxygen-derived free radicals and oxidants

Our relationship with oxygen is, at best, a difficult one to manage. Occasionally, under normal biological conditions, oxygen does manage to steal away electrons from other molecules by nonenzymatic autoxidations. Because it cannot accommodate a spin-matched pair, it must settle for stealing electrons one at a time. This breaking up of electron pairs results in free radical formation. The one-electron reduction product of oxygen is the superoxide radical, O2•−. If two electrons are transferred,

The evolution of the aerobic lifestyle

Life on this planet first evolved in a reducing atmosphere. It was not until photosynthetic algae appeared that oxygen began to be introduced into the atmosphere in ever increasing quantities. This shift from a reducing environment to an oxidizing one undoubtedly resulted in some serious evolutionary pressures. One might be surprised when examining modern metabolic pathways to find that very few enzymes actually deal with molecular oxygen, despite the fact that our bioenergetics scheme is

The evolution of antioxidants and antioxidant enzymes

In addition to evolutionary attempts to avoid the production of reactive byproducts of oxidative metabolism, another very important direction was the ability to synthesize or accumulate antioxidants—molecules that would avidly react with and annihilate active oxygen species before they could inflict oxidative damage to vital components, such as DNA or cell membranes. The result was hundreds of kinds of such antioxidant molecules, especially in plants. Among the most successful of these

The reactivity and toxicity of superoxide radical

Although the chemical reactivity of the superoxide radical is modest, its toxicity is quite easily demonstrated. Escherichia coli contains three genes for SODs: one enzyme uses manganese as its cofactor, one uses iron, one uses copper and zinc. Disruption of the two major genes encoding the manganese and iron enzymes results in a bacterium unable to grow aerobically in minimal medium but still able to grow anaerobically (7). Aerobically, it displays multiple auxotrophies and can grow if all

If life gives you lemons, make lemonade

One of the most fascinating aspects of evolution is the ability to make the best of a bad situation, to make a silk purse from the proverbial sow’s ear. There are clear examples of how active oxygen products, which we generally try to avoid producing at all costs, can actually be put to constructive uses. The best example is the evolution of our phagocytic NADPH oxidase. When first discovered as a biologic metabolite, it appeared that the superoxide radical was simply a noxious cytotoxic

Redox regulation of gene expression

If oxidative status can signal cells to respond in various ways, we must ask how these signals are transduced, carried, and interpreted, especially by the cell’s genetic machinery. The study of redox regulation of gene expression has exploded in recent years and clearly suggests that oxidants are major determinants of gene expression. Reactive oxygen intermediates have been implicated in the activation of a variety of kinases [such as the Src kinase family (32); protein kinase C (33);

Oxidative stress and malignancy

Reining in a cell’s biological imperative to proliferate and placing constraints on the natural inclination to replicate DNA and divide is no small feat. Indeed, it may require more sophisticated cellular engineering to squelch the desire to proliferate than to promote it. The connection between mild oxidative stress and cellular growth may date back to the primordial soup. When food is plentiful, metabolism is running at full speed, and there is sufficient energy to support cell division, the

Oxidative stress and human disease

Perhaps the most noteworthy observation concerning the role of oxidative stress in human disease is the commonality of it. Oxidative stress is now thought to make a significant contribution to all inflammatory diseases [arthritis 26, 50, vasculitis (51), glomerulonephritis (52), lupus erythematosus (53), adult respiratory distress syndrome (54)], ischemic diseases [heart disease (55), stroke (56), intestinal ischemia (57)], hemochromatosis (58), acquired immunodeficiency syndrome (AIDS) (59),

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