Free radicals and antioxidants in health and disease by K. Bagchi and S. Puri

Introduction
It is ironic that oxygen, an element indispensable for life can, under certain situations, have severely deleterious effects on the human body. Most of the potentially harmful effects of oxygen are due to the formation and activity of a number of chemical compounds, known as reactive oxygen species, which have a tendency to donate oxygen to other substances. Many such reactive species are free radicals and have a surplus of one or more free-floating electrons rather than having matched pairs and are, therefore, unstable and highly reactive. Types of free radicals include the hydroxyl radical (OH.), the superoxide radical (O.₂), the nitric oxide radical (NO.) and the lipid peroxyl radical (LOO.). 

Production of free radicals in the human body
Free radicals and other reactive oxygen species are derived either from normal essential metabolic processes in the human body or from external sources such as exposure to X-rays, ozone, cigarette smoking, air pollutants and industrial chemicals.
Free radical formation occurs continuously in the cells as a consequence of both enzymatic and non-enzymatic reactions (Figure 1). Enzymatic reactions which
serve as sources of free radicals include those involved in the respiratory chain, in phagocytosis, in prostaglandin synthesis and in the cytochrome P450 system. Free radicals also arise in non-enzymatic reactions of oxygen with organic compounds as well as those initiated by ionizing radiations. Some internally generated sources of free radicals are [1]:

• mitochondria
• phagocytes
• xanthine oxidase
• reactions involving iron and other transition metals
• arachidonate pathways
• peroxisomes
• exercise
• inflammation
• ischaemia/reperfusion.

Some externally generated sources of free radicals are [1]:

• cigarette smoke
• environmental pollutants
• radiation
• ultraviolet light
• certain drugs, pesticides, anaesthetics and industrial solvents
• ozone.

With electrons unhinged, free radicals roam the body, wreaking havoc. The free radical, in an effort to achieve stability, at
tacks nearby molecules to obtain another electron and, in doing so, damages those molecules. This situation can be compared to letting a bachelor into a dance where people have come as couples. The bachelor begins cutting in, each time leaving another bachelor, so the breaking up of couples spreads through the dance floor.
If free radicals are not inactivated, their chemical reactivity can damage all cellular macromolecules including proteins, carbohydrates, lipids and nucleic acids (Figure 2). Their destructive effects on proteins may play a role in the causation of cataracts. Free radical damage to DNA is also implicated in the causation of cancer and its effect on LDL cholesterol is very likely responsible for heart disease. In fact, the theory associating free radicals with the aging process has also gained widespread acceptance (see Box 1). 

The free radical diseases
A well accepted fact is the increasing incidence of disease with advancing age. A plausible explanation for the association of age and disease is based on the implication of free radical reactions in the pathogenesis of several disorders.
Free radical reactions are expected to produce progressive adverse changes that accumulate with age throughout the body. Such "normal" changes with age are relatively common to all. However, superimposed on this common pattern are patterns influenced by genetics and environmental differences that modulate free radical damage. These are manifested as diseases at certain ages determined by genetic and environmental factors. Cancer and atherosclerosis, two major causes of death, are salient "free radical" diseases. Cancer initiation and promotion is associated with chromosomal defects and oncogene activation. It is possible that endogenous free radical reactions, like those initiated by ionizing radiation, may result in tumour formation. The highly significant correlation between consumption of fats and oils and death rates from leukaemia and malignant neoplasia of the breast, ovaries and rectum among persons over 55 years may be a reflection of greater lipid peroxidation [2]. Studies on atherosclerosis reveal the probability that the disease may be due to free radical reactions involving diet-derived lipids in the arterial wall and serum to yield peroxides and other substances. These compounds induce endothelial cell injury and produce changes in the arterial walls [3].
Free radicals, however, are not always harmful. They also serve useful purposes in the human body. Several observations indicate that the oxygen radicals in living systems are probably necessary compounds in the maturation processes of cellular structures. Furthermore, white blood cells release free radicals to destroy invading pathogenic microbes as part of the body's defence mechanism against disease. Hence, the complete elimination of these radicals would not only be impossible, but also harmful.