Chapter 45

After studying this chapter, you should be able to:

• Describe the damage caused to DNA, lipids, and proteins by free radicals, and the diseases associated with radical damage.
• Describe the main sources of oxygen radicals in the body.
• Describe the mechanisms and dietary factors that protect against radical damage.
• Explain how antioxidants can also act as pro-oxidants, and why intervention trials of antioxidant nutrients have generally yielded disappointing results.

Free radicals are formed in the body under normal conditions. They cause damage to nucleic acids, proteins, and lipids in cell membranes and plasma lipoproteins. This can cause cancer, atherosclerosis and coronary artery disease, and autoimmune diseases. Epidemiological and laboratory studies have identified a number of protective antioxidant nutrients: selenium, vitamins C and E, β-carotene, and other carotenoids, and a variety of polyphenolic compounds derived from plant foods. Many people take supplements of one or more antioxidant nutrients. However, intervention trials show little benefit of antioxidant supplements except among people who were initially deficient, and many trials of β-carotene and vitamin E have shown increased mortality among those taking the supplements.

### Free Radical Reactions Are Self-Perpetuating Chain Reactions

Free radicals are highly reactive molecular species with an unpaired electron; they persist for only a very short time (of the order of 10–9 to 10–12 sec) before they collide with another molecule and either abstract or donate an electron in order to achieve stability. In so doing, they generate a new radical from the molecule with which they collided. The main way in which a free radical can be quenched, so terminating this chain reaction, is if two radicals react together, when the unpaired electrons can become paired in one or other of the parent molecules. This is a rare occurrence, because of the very short half-life of an individual radical and the very low concentrations of radicals in tissues.

The most damaging radicals in biological systems are oxygen radicals (sometimes called reactive oxygen species)—especially superoxide, , hydroxyl, OH, and perhydroxyl, O2H. Tissue damage caused by oxygen radicals is often called oxidative damage, and factors that protect against oxygen radical damage are known as antioxidants.

### Radicals Can Damage DNA, Lipids, and Proteins

Interaction of radicals with bases in DNA can lead to chemical changes that, if not repaired (Chapter 35), may be inherited in daughter cells. Radical damage to unsaturated fatty acids in cell membranes and plasma lipoproteins leads to the formation of lipid peroxides, then highly reactive dialdehydes that can chemically modify proteins and nucleic acid bases. Proteins are also subject to direct chemical modification by interaction with radicals. Oxidative damage to tyrosine residues in proteins can lead to the formation of dihydroxyphenylalanine that can undergo nonenzymic reactions leading to further formation of oxygen radicals (Figure 45–1).

###### Figure 45–1

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