Free radicals in health and disease

Molecular and Cellular Biochemistry -     

Free radicals and disease in man

Free radicals and related activated electronic species are produced in biological systems in antimicrobial defense, through the action of the mixed function monooxygenases, by various oxidative enzymes such as xanthine oxidase, and by autooxidations mediated by such agents as heavy metals or quinones. While the evidence is circumstantial, excessive unconfined or inappropriate production of radical species in inflammation, the metabolism of exogenous chemicals, or through autooxidation probably plays a significant role in human disease.     

Free radicals and disease.

Free radicals and reactive oxygen species (ROS) have been associated with the etiology and/or progression of a number of diseases and in aging. Many of the proteins oxidatively modified by free radicals contain side-chain carbonyl derivatives, which can be used as markers for protein oxidation. The protein carbonyl content has been quantitated as a function of age for human cultured dermal fibroblasts, lens, and brain tissue. These data were analyzed using a simple autocatalytic model with the assumption that free radicals randomly oxidize proteins or peptides to form carbonyl derivatives and lead to their inactivation. The carbonylated proteins and peptides are highly susceptible to proteolytic degradation. Implication of free radicals in aging and in age-dependent susceptibility to neurodegenerative diseases will be discussed in light of this simplified kinetic model.     

Free radicals in exhaustive physical exercise: mechanism of production, and protection by antioxidants

Moderate exercise is a healthy practice. However, exhaustive exercise generates free radicals. This can be evidenced by increases in lipid peroxidation, glutathione oxidation, and oxidative protein damage. It is well known that activity of cytosolic enzymes in blood plasma is increased after exhaustive exercise. This may be taken as a sign of damage to muscle cells. The degree of oxidative stress and of muscle damage does not depend on the absolute intensity of exercise but on the degree of exhaustion of the person who performs exercise. Training partially prevents free radical-formation in exhaustive exercise. Treatment with antioxidants such as vitamins C or E protects in part against free radical-mediated damage in exercise. Xanthine oxidase is involved in free-radical formation in exercise in humans and inhibition of this enzyme with allopurinol decreases oxidative stress and muscle damage associated with exhaustive exercise. Knowledge of the mechanism of free-radical formation in exercise is important because it will be useful to prevent oxidative stress and damage associated with exhaustive physical activity.     

Free radicals in aging

Summary Aging is the progressive accumulation of changes with time that are responsible for the ever-increasing likelihood of disease and death. These irreversible changes are attributed to the aging process. This process is now the major cause of death in the developed countries. This fact is obscured by the protean nature of the contributions of this process to the events which terminate life.The aging process may be due to free radical reations. This theory is supported by: 1) studies on the origin and evolution of life; 2) the numerous studies of the effect of ionizing radiation on living systems; 3) life span experiments in which the diet was modified so as to alter endogenous free radical reaction levels; 4) the plausible explanations it provides for aging phenomena; and 5) the growing number of studies which implicate free radical reactions in the pathogenesis of specific diseases.The relationship between aging and diseases involving free radical reactions seems to be a direct one. Modulation of the normal distribution of deleterious free radical reaction-induced changes throughout the body by genetic and environmental differences between individuals results in patterns of change, in some sufficiently different from the normal aging pattern to be recognized as disease. The growing number of free radical diseases includes the two major causes of death, cancer and atherosclerosis.It is reasonable to expect on the basis of present data that a judicious selection of diets and antioxidant supplements will increase the healthy, active life span by 5–10 or more years.     

Free radicals and senescence

There is a significant body of experimental evidence that a rise in intracellular reactive oxygen species (ROS) contributes to senescence. Here we review experiments where entry into senescence has been evaluated in cells whose intracellular ROS levels have been modulated by growth in either high or low ambient oxygen concentrations, or where the cellular antioxidant status has been perturbed. In addition, we discuss the observations that senescence triggered by oncogene expression also appears to be in part mediated by a rise in ROS levels. Finally, we discuss the emerging evidence that in vivo senescence might also be triggered by a rise in cellular oxidant levels. Although these data tend to support a role for ROS in mediating senescence, significant questions remain as to whether ROS act in a random or specific fashion and what precise oxidant species acts as the potential senescence trigger.     

Free radicals and diabetes

The role of active oxygen species in diabetes is discussed in this review. Type I diabetes is caused by destruction of the pancreatic beta cells responsible for producing insulin. In humans, the diabetogenic process appears to be caused by immune destruction of the beta cells; part of this process is apparently mediated by white cell production of active oxygen species. Diabetes can be produced in animals by the drugs alloxan and streptozotocin; the mechanism of action of these two drugs is different, but both result in the production of active oxygen species. Scavengers of oxygen radicals are effective in preventing diabetes in these animal models. Not only are oxygen radicals involved in the cause of diabetes, they also appear to play a role in some of the complications seen in long-term treatment of diabetes. Changes in antioxidants in the diabetic state and their consequences are discussed.     

Free radicals and their interpretations

Oxygen free radicals can be blamed for evoking gastric mucosal damage, because of the protective effect of some lipid soluble free radical scavengers (vitamin A related compounds, Vitamin E). Direct determination of free oxygen radicals related chemical entities in the gastric tissue during ulcerogenesis yielded controversial results. Aluminum antacid compound together with acid binding property exhibited cytoprotection too, elevating the tissue PGE2 level substantially. Magnesium containing antacid according to our model experiments on red blood cells damage by free radicals, is capable to bind free radicals as well as to counteract with the dangerous intracellular calcium accumulation. It has been concluded that aluminum-magnesium antacid has a cytoprotective effect via: 1. acid binding; 2. prostaglandin generation; 3. free radical scavenging; 4. calcium antagonist activity.     

Free radicals in iron-containing systems

All oxidative damage in biological systems arises ultimately from molecular oxygen. Molecular oxygen can scavenge carbon-centered free radicals to form organic peroxyl radicals and hence organic hydroperoxides. Molecular oxygen can also be reduced in two one-electron steps to hydrogen peroxide in which case superoxide anion is an intermediate; or it can be reduced enzymatically so that no superoxide is released. Organic hydroperoxides or hydrogen peroxide can diffuse through membranes whereas hydroxyl radicals or superoxide anion cannot. Chain reactions, initiated by chelated iron and peroxides, can cause tremendous damage. Chain carriers are chelated ferrous ion; hydroxyl radical .OH, or alkoxyl radical .OR, and superoxide anion O2-. or organic peroxyl radical RO2.. Of these free radicals .OH and RO2. appear to be most harmful. All of the biological molecules containing iron are potential donors of iron as a chain initiator and propagator. An attacking role for superoxide dismutase is proposed in the phagocytic process in which it may serve as an intermediate enzyme between NADPH oxidase and myeloperoxidase. The sequence of reactants is O2----O2-.----H2O2----HOCl.     

Free radicals and anti-inflammatory drugs

It is widely accepted that oxygen radicals and other activated oxygen species are potent mediators or modulators of acute and chronic inflammation. They are common products of cellular metabolism, where their concentrations are controlled by different protective mechanisms such as superoxide dismutase, catalase etc. In addition to their destructive effects on various macromolecules, oxygen radicals or their products are beneficial e.g., in killing bacteria. Oxygen radicals are also closely related to arachidonic acid metabolism, prostanoids (cyclo-oxygenase pathway) and leukotrienes (lipoxygenase pathway) as well as to lipid peroxidation in general. Also, the classical mediators of inflammation, histamine and bradykinin, may be connected with the release of oxygen radicals. In addition to the earlier described inhibition of formation of prostanoids, non-steroidal anti-inflammatory drugs can inhibit production of free radicals or scavenge those already formed. Antirheumatic penicillamine and allopurinol used in the treatment of gout also act on oxygen radicals. New anti-inflammatory compounds with antioxidant properties will be developed in the near future.