Free radical injury and antioxidants

The organic solvent Carbon tetra chloride (CCl4) is used in the dry cleaning industry. The Carbon tetra chloride (CCl4) is metabolized in the body by cytochrome P450 enzyme system to form a free radical species CCl3 . This highly reactive species causes a chain reaction of lipid peroxidation, particularly in the liver, that can lead to hepatocellular necrosis. The cells have developed enzymes and other molecules to help them protect against the free radical damage. Some dietary components also act as anti-oxidants. Which of the following dietary components can provide some protection against free radical injury?

A. Glutamine

B. Linoleic acid

C. Ascorbic acid

D. Folic acid

E. Iron.

The correct option is C- Ascorbic acid.

Basic concept

Reactive oxygen species (ROS) are highly reactive oxidizing agents belonging to the class of free-radicals. A free radical is any compound (not necessarily derived from oxygen) which contains one or more unpaired electrons. The most common ROS that have potential implications include-Superoxide (O2) anion, hydrogen peroxide (H2O2), peroxyl (ROO) radicals, and the very reactive hydroxyl (OH) radicals.

The nitrogen-derived free radical nitric oxide (NO.) and peroxynitrite anion (ONOO) also appear to play a significant role in the causation of diseases. The ultimate effect of (NO) depends upon its concentration and interactions with hydrogen peroxide. Peroxynitrite anion may be formed in vivo from Superoxide and nitric oxide.

“Oxidative stress” is a condition associated with an increased rate of cellular damage induced by oxygen and oxygen-derived oxidants. Reactive oxygen species (ROS) are highly reactive with lipids, proteins, and DNA, causing oxidative damage to these cellular macromolecules. This damage, termed oxidative stress, accumulates over time and is thought to contribute to both disease pathology and the aging process.

Reactive oxygen species (ROS) have been implicated in over a hundred of disease states which range from arthritis and connective tissue disorders to carcinogenesis, aging, toxin exposure, physical injury, infection, and acquired immunodeficiency syndrome.

Cellular mechanisms that exist to counteract ROS include stabilization by enzymes such as superoxide dismutase and catalase, and direct scavenging by antioxidant molecules such as glutathione (GSH), a major intracellular antioxidant; cysteine, a precursor of GSH and a major extracellular antioxidant in plasma; vitamin E, a major lipid soluble antioxidant; and ascorbate, a critical intracellular and extracellular antioxidant.

Role of vitamin C

The primary function of vitamin C (ascorbic acid) is the production of collagen, which forms the basis for connective tissue in bones, teeth, and cartilage. It also plays an important role in wound healing, immunity, and the nervous system, and acts as a water-soluble antioxidant.

Vitamin C is the major water-soluble antioxidant within the body. The vitamin readily donates electrons to break the chain reaction of lipid peroxidation. The water-soluble properties of vitamin C allow for the quenching of free radicals before they reach the cellular membrane. Tocopherol and glutathione also rely on Ascorbic acid (AA) for regeneration back to their active isoforms (figure).

Because vitamin C is water-soluble, its antioxidant functions take place in aqueous body compartments. It also helps protect low-density lipoprotein cholesterol (LDL-C) against free radical damage. As an antioxidant, it helps protect against cancer, cardiovascular disease, and certain effects of aging.

Role of vitamin E

Unlike other vitamins, which are involved in metabolic reactions, it appears that the primary role of vitamin E is to act as an antioxidant. Vitamin E is incorporated into the lipid portion of cell membranes and other molecules, protecting these structures from oxidative damage and preventing the propagation of lipid peroxidation. Vitamin E appears to have protective effects against cancer, heart disease, and complications of diabetes.

Antioxidant role of vitamin E

The main function of vitamin E is as a chain-breaking, free-radical trapping antioxidant in cell membranes and plasma lipoproteins by reacting with the lipid peroxide radicals formed by peroxidation of polyunsaturated fatty acids. The tocopheroxyl radical product (oxidized form) is relatively unreactive, and ultimately forms nonradical compounds. Commonly, the tocopheroxyl radical is reduced back to tocopherol by reaction with vitamin C from plasma. Ascorbate is essential for maintaining vitamin E in its reduced, active form. Ascorbate is oxidized to dehydroascorbate in plasma, which is recycled back to ascorbate by GSH as well as by several enzyme systems in erythrocytes, neutrophils, endothelial cells and hepatocytes (See figure). GSH itself gets oxidized during this process and is converted back to its reduced form by Glutathione reductase utilizing  NADPH as the reductant.  GSH is also utilized by Selenium containing Glutathione Peroxidase enzyme for decomposing H2O2.



Figure – The interrelationship between vitamin C, E and Glutathione. (R, free radical)

As an antioxidant, vitamin E plays a protective role in many organs and systems. Vitamin E is necessary for maintaining a healthy immune system, and it protects the thymus and circulating white blood cells from oxidative damage. Also, it may work synergistically with vitamin C in enhancing immune function. Recent research evidence indicates that the combined use of high doses of vitamin C and vitamin E helps prevent Alzheimer’s disease. In the eyes, vitamin E is needed for the development of the retina and protects against cataracts and macular degeneration.

Role of Carotenoids

The only specific effect of carotenoids in humans is to act as source of vitamin A in the diet, but they also have important antioxidant actions. The latter are based on the carotenoids’ ability to quench singlet oxygen and trap peroxyl radicals, thereby preventing lipid peroxidation.

As a result, carotenoids protect against the development of cancer, cardiovascular disease, and ocular disorders. Carotenoids also affect cell growth regulation and gene expression. Diets low in carotenoids may lead to increased risk of cancer and heart disease.

As regards other options

A. Glutamine- is an amino acid; it has no role in defense against oxidative stress.

B.  Linoleic acid- It is an ω 6 fatty acid (Polyunsaturated fatty acid), it can itself get oxidized to free radical form to initiate lipid peroxidation, it has no role in defense.

D.  Folic acid- has no role as an antioxidant.

E.  Iron- Free iron is toxic to the body; it leads to generation of free radicals which  is why iron is always present in the body in the bound form.


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