Notes on Free Radicals | Herbal Drugs

Read this article to learn about Free Radicals. After reading this article you will learn about: 1. Characteristics of Free Radicals 2. Generation of Free Radicals 3. Beneficial Activities 4. Harmful Activities.

Characteristics of Free Radicals:

ROS and RNS are the terms collectively describ­ing free radicals and other non-radical reactive derivatives called oxidants. A molecule with one or more unpaired electron in its outer shell is called a free radical.

Free radicals are formed from mole­cules via the breakage of a chemical bond such that each fragment keeps one electron, by cleav­age of a radical to give another radical and via redox reaction. These radicals are hydroxyl (OH^•), super­oxide (O₂^•−), nitric oxide (NO^•), nitrogen dioxide (NO₂), peroxyl (ROO^•) and lipid peroxyl (LOO^•).

Also, hydrogen peroxide (H₂O₂), ozone (O₃), sin­glet oxygen (1O₂), hypochlorous acid (HOCI), ni­trous acid (HNO₂), per-oxy-nitrite (ONOO⁻), di-nitrogen trioxide (N₂O₃), lipid peroxide(LOOH), are not free radicals and generally called oxidants, but can easily lead to free radical reactions in living organisms.

Biological free radi­cals are thus highly unstable molecules that have electrons available to react with various organic substrates such as lipids, proteins, DNA. These oxidants can dam­age cells by starting chemical chain reactions such as lipid peroxidation, or by oxidizing DNA or pro­teins. 

Damage to DNA can cause mu­tations and possibly cancer, if not reversed by DNA repair mechanisms, while damage to proteins caus­es enzyme inhibition, denaturation and protein degradation.

Generation of Free Radicals:

Formation of ROS and RNS can occur in the cells by two ways: enzymatic and non-enzymatic re­actions. Enzymatic reactions generating free rad­icals include those involved in the respiratory chain, the phagocytosis, the prostaglandin synthe­sis and the cytochrome P₄₅₀ system.

The superox­ide anion radical (O₂^•−) is generated via several cellular oxidase systems such as N ADPH oxidase, xanthine oxidase, peroxidases and then it partici­pates in several reactions yielding various ROS and RNS which are hydrogen peroxide, hydroxyl radical (OH^•), per-oxy-nitrite (ONOO-), hypochlo­rous acid (HOCI), etc.

Non-radical H₂O₂ is pro­duced by the action of several oxidase enzymes, including amino acid oxidase and xanthine oxi­dase. Hydroxyl radical (OH^•), the most reactive free radical in vivo, is formed by the reaction of O₂^•− with H₂O₂ in the presence of Fe²⁺ or Cu⁺⁺ (catalyst). This reaction is known as the Fenton reaction.  

2Fe³⁺ + Ascorbate → 2Fe²⁺ + De-hydro-ascorbate

2Fe²⁺ + 2H₂O_z → 2Fe³⁺ + 2OH^• + 20H⁺

The neutrophil-derived enzyme, myeloperox­idase, which oxidizes chloride ions in the pres­ence of H₂O₂, produces hypochlorous acid (HOCI). Nitric oxide radical (NO^•) is formed in biological tissues from the oxidation of L-arginine to citrulline by nitric oxide synthase.

Free radicals can be pro­duced from non-enzymatic reactions of oxygen with organic compounds as well as those initiat­ed by ionizing radiations. The non-enzymatic process can also occur during oxidative phospho­rylation (i.e. aerobic respiration) in the mitochon­dria.

ROS and RNS are generated from either en­dogenous or exogenous sources. Endogenous free radicals are generated from immune cell activa­tion, inflammation, mental stress, excessive exer­cise, ischemia, infection, cancer, aging.

Exogenous ROS/RNS result from air and water pollution, cig­arette smoke, alcohol, heavy or transition metals (Cd, Hg, Pb, Fe, As), certain drugs (cyclosporine, tacrolimus, gentamycin, bleomycin), industrial solvents, cooking (smoked meat, used oil, fat), ra­diation.

Beneficial Activities of Free Radicals:

At low or moderate concentrations, ROS and RNS are necessary for the maturation process of cellu­lar structures and can act as weapons for the host defense system. Indeed, phagocytes (neutrophils, macrophages, monocytes) release free radicals to destroy invading pathogenic microbes as part of the body’s defense mechanism against disease.

The importance of ROS production by the immune system is clearly exemplified by patients with granulomatous disease due to defective mem­brane-bound NADPH oxidase system which makes them unable to produce the superoxide anion radical (O₂^•−), thereby resulting in multiple and persistent infection.

Other beneficial effects of ROS and RNS involve their physiological roles in the function of a number of cellular signaling systems.

Their production by non-phagocytic NADPH oxidase isoforms plays a key role in the regulation of intracellular signaling cascades in various types of non-phagocytic cells including fibroblasts, endothelial cells, vascular smooth muscle cells, cardiac myocytes, and thy­roid tissue. For example, nitric oxide (NO) is an intercellular messenger for modulating blood flow, thrombosis, and neural activity.

In brief, ROS/RNS at low or moderate lev­els are vital to human health cytic NADPH oxi­dase isoforms plays a key role in the regulation of intracellular signaling cascades in various types of non-phagocytic cells including fibroblasts, en­dothelial cells, vascular smooth muscle cells, car­diac myocytes, and thyroid tissue.

Harmful Activities of Free Radicals and Pathogenesis:

An oxidative stress, a deleterious process that can seriously alter the cell membranes and other struc­tures such as proteins, lipids, lipoproteins, and deoxyribonucleic acid (DNA) due to generation of excess free radicals and oxidants.

Oxidative stress can arise when cells cannot adequately de­stroy the excess of free radicals formed. In other words, oxidative stress results from an imbalance between formation and neutralization of ROS/RNS. For example, hydroxyl radical and per-ox­y-nitrite in excess can damage cell membranes and lipoproteins by a process called lipid peroxida­tion.

This reaction leads to the formation of malondialdehyde (MDA) and conjugated diene compounds, which are cytotoxic and mutagenic. Proteins may also be damaged by ROS/RNS, leading to structural changes and loss of enzyme activity.

Oxidative damage to DNA leads to the formation of different oxidative DNA lesions, which can cause mutations. The body has several mechanisms to counteract these attacks by using DNA repair enzymes and/or antioxidants.

If not regulated properly, oxidative stress can induce a variety of chronic and degenerative diseases as well as the aging process and some acute pathologies like stroke, atherosclerosis, cancer, cardiovascular disease etc..