The realization that reactive oxygen species (ROS) and oxidative stress (OS) play an important role in the etiology and progress of major human degenerative diseases has triggered enormous and worldwide interest in endogenous and exogenous antioxidants. There is now abundant evidence that substances in fruits and vegetables are potent preventives of various diseases, especially cancer, heart disease, diabetes and cataracts. With these recent developments in scientific knowledge, it has been now firmly established that there is a strong link between food factors and prevention of diseases. It would be therefore pertinent to gain a better insight into the key food factors that are responsible for health benefits and the way they work.
Over the last ten years or so, we have seen a plethora of studies looking at the importance of vitamin E and other antioxidant nutrients in cardiovascular disease. These studies have given rise to very carefully controlled double blind trials with nutrient supplements. These trials in turn have resulted in specific effects of the classic vitamins, as well as more newly recognized antioxidants, such as beta carotene on the morbidity and indeed mortality of different population groups.
Generation of ROS
ROS comprises of superoxide anion radical (O-2), peroxide anion (O22-) and single oxygen (1O2). These are highly reactive entities produced from molecular oxygen (O2) by gaining electrons (-OH). The most highly reactive species of ROS is formed by dismutation of peroxide catalysed by Fe2+. The hypochlorite ion (OCl-) is yet another highly reactive oxygen species, which together with the former ROS is produced by leucocytes to kill the invading microorganizations.
The free radial nitric oxide (NO) identical with endothelium derived relaxing factor (EDRF), is an important cytotoxic molecule, active in defence against malignant cells, fungi and protozoa. It results in vasodilation and inflammation. It is generated from L-arginine and contributes to endogenous nitrosation of secondary amines. Its formation decreases in old age, hence the increase in fungal infection and malignancies at that time.
ROS are formed spontaneously by many biological processes and may be considered as a measure of biological inefficiency. They are formed by electron leakage from membranes and from inadequately complete reactions. The released electrons reduce the molecular oxygen stepwise from superoxide anion and then peroxide. Electron leakage occurs continuously from the mitochondrial membranes and from the endoplasmic reticulum. They are also formed from the futile cycling of the various cytochromes.
ROS are the mediators and information and through this they interact with plalelets, neutorphils, macrophages and other cells. They get involved in the synthesis of eicosanoids and activation and release of various cytokines. This propagates the inflammatory process from one oxygen system (liver) to another (kidney, lungs etc). This results in tissue OS and multiple system organ failure. Generation of ROS in experimental animals by fasting or by exposure to ether anaesthesia, result in tissue OS by depletion of tissue glutathione (GSH). Restoration of the GSH can prevent the OS and tissue injury.
ROS medicated inflammation is involved in the pathegenesis of infectious diseases, including tuberculosis and septic shock. It is also involved in immune and autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. More recent studies have also implicated the involvement of ROS in cancer, aetherosclerosis, hepatitis, AIDS, alzeimer, dementia and respiratory distress syndrome. Molecular mechanism of ROS toxicity and ROS mediated diseases include:
■ Oxidation of vital thiol compounds to disulphides
■ Loss of tissue GSH
■ Impairment of energy generation,
■ Inhibition of Ca2+ transport and electrolyte homeostasis
■ DNA strand cleavage
■ The initiation and promotion of mutation and cacinogensis
Biological defence against ROS injury
Biological defence against ROS comprises of a complete array of endogenous antioxidant enzymes, numerous endogenous antioxidant factors, including GSH and other tissue thiols, heam proteins, coenzyme, bilirubin, urates and primarily the antioxidant vitamins.
Antioxidant defence
The cascade of endogenous antioxidant enzymes requires energy to maintain the living system in the reduced state. The endogenous factors operate a number of repair systems. They are:
■ Reduction of disulphides, peroxides, quinones, etc. by GSH, with GSH reductase and GSH peroxidase
■ Radical scavenging by the GSH / ascorbate / tocopherol system
■ Reduction of soluble peroxides by GSH peroxidase (GPX)
■ Reduction of phospholipid membrane peroxides by GSH phospholipid peroxidase (PMGPX)
■ Phospholipid membrane integrity, methylation of ethanoamine to choline, to prevent electron loss
■ Defence against NO nitrosation in stomach by ascorbate
Nutritional antioxidant defence
The various mechanisms for nutritional defence and disease prevention are:
■ ROS scavanging
■ Reduction of peroxides and repair of peroxidized biological membranes
■ Sequestation of iron to decrease ROS formation
■ Utilization of dietary lipids (rapid energy production and ROS scavanging by short chain fatty acids, ROS scavanging by cholesteryl esters) and alternative biological pathways as occur in stomach cancer, multiple system organ failure and diabetes
As we have seen, dietary, vitamin C, vitamin E and retinoids provide an integrated antioxidant system, which is self-generating. As long as the subject is well nourished, the integrated antioxidant system protects the individual against OS system and reverses the subsequent oxidative damage.
(The author is pharmaceutical technical consultant, based in Mumbai)