Free Radicals

Free radicals are harmful chemical species normally produced in the body as a by-product of utilizing oxygen to produce energy. The body purposely creates certain free radicals for specific purposes, but most free radicals in the body are formed unintentionally and are undesirable agents that can do damage that leads to cancer, heart disease, arthritis, accelerated aging and diseases and disorders associated with aging.

Simply, a free radical is an active part of a molecule. Another simple description that holds true for the vast majority of biochemical situations is that a free radical is merely a chemical species with an odd number of electrons. As explained later, all chemical species having an odd number of electrons are free radicals, but there are chemical species that have an even number of electrons that are also free radicals, although they rarely encountered in biochemistry. A slightly better description is that a free radical is a molecule or atom containing one or more lone or "unpaired" electron(s). This is not to be confused with an "ion" which is a chemical species with an imbalance between the numbers of negatively-charged electrons and positively-charged protons. Free radicals can be electronically neutral or charged. If a free radical is charged, it is called a "radical ion." The energy of interest in free radicals is magnetic rather than electrical.

Atoms that are grouped together more or less as a unit in a molecule can be called a radical. This group or "radical" generally stays together during a chemical reaction and can be transferred from molecule to molecule. However, when speaking of "free radicals," radical simply refers to the remainder of an atom or molecule after an electron has been removed from a pair of electrons in an electronic orbital.

Electrons travel about the nucleus of an atom or molecule in paths similar to the manner in which planets travel around the Sun. Atoms and molecules have various layers or shells of electrons orbiting a nucleus. Electronic shells and orbitals are merely regions in which there is a high probability of finding an electron. These shells and orbitals are determined by the structure of the atom or molecules. Filled atomic electronic shells hold 2,8,18 and 32 electrons, and electronic orbitals hold a maximum of two electrons.

Traveling within these atomic or molecular electronic shells are one or more electronic orbitals that can hold a pair of electrons. Electrons also spin about on their axis like the Earth spins on its axis to give us day and night. Electrons found in atoms and molecules tend to exist in pairs. Normally, two electrons are coupled or paired in an orbital with their spins in opposing directions. By convention, these spins are described in quantum mechanics as being either "up" or "down." Since the spins of electrons normally (at standard conditions in what is termed the "ground state," is usually a "singlet" state) are in opposing directions, their magnetic vectors cancel each other. The opposing spins of these paired electrons result in a lower energy state than resulting from other groupings. When an electron is by itself in an orbital, there is extra energy available due to its spin.

When there is a lone electron the radical will have a magnetic vector and is said to be "paramagnetic."

The reason that the simple definition given earlier is accurate is that all atoms and molecules that have an odd number of electrons must have at least one electron that is in an orbital by itself. However, this simpler definition doesn’t take into account such things as di-radicals, which are chemical species having two lone or unpaired electrons, and atoms of many elements, which are free radicals because they contain lone electrons in orbitals even though the total number of electrons may be even. Transition metal complexes that have one or more unpaired electrons associated with the metal are not generally referred to as free radicals.

All chemical species with an odd number of electrons are free radicals, but there are some free radicals that have an even number of electrons, but generally speaking, those exceptions are not the free radicals generally dealt with in biochemistry.

The simplest free radical is the hydrogen atom as it has only one electron. The hydrogen molecule has two electrons and is not a free radical. Other common free radicals include the oxygen diatomic molecule (O2), superoxide anion radical (O2.-), hydroxyl radical (HO.), alkoxyl radical (RO.) and the peroxyl radical (ROO.)

Free Radical Propagation: Being that free radicals have higher energy due to their unpaired electron, they have a tendency to be reactive with other molecules. This is simply described as "an effort to regain its lost electron and become stable." Because of this, most free radicals are unstable and very reactive. Thus, free radicals can be harmful to body components. Most free radicals call pull an electron from most biochemical compounds. It has been estimated that each cell in the body is hit by approximately 10,000 free radicals every day.

A few free radicals are stable molecules. Nitric oxide is an example of a free radical being a stable molecule.

When a free radical is produced in a chemical system, there is generally a propagation of damage. When a free radical reacts with another compound, it generally removes an electron from that compound which, of course, leaves it with an odd number of electrons and has now become a free radical. This series of reactions can continue until the reaction is terminated by a species that can alter electron spin or the last free radical formed is of low energy and has insufficient energy to continue the propagation. Antioxidants are compounds that quench free radical reactions because their resulting free radicals have relatively low energy. The amount of damage occurred is dependent upon both the number of free radical hits and the amount of protection by antioxidants.

Oxygen Free Radicals: Most free radicals produced in the body are a by-product of oxygen metabolism, i. e., oxygen being utilized to produce energy from food components. Some oxygen free radicals are extremely harmful to the body. Actually, the oxygen molecule itself, a diatomic molecule consisting of two oxygen atoms, is a bi-radical. The ground state diatomic oxygen molecule has two unpaired electrons, each located in a different non-bonding orbital. Thus, it has two odd electrons. But, the oxygen molecule – which is actually two free radicals united – is not particularly dangerous because each of the spins of the unpaired electrons happen to be in the same direction. (Thus, the ground state of oxygen is the "triplet" state, rather than the singlet state.) If oxygen’s unpaired electrons were spinning in opposite directions, oxygen would be a very reactive radical.

The first excited state of oxygen is the singlet state. Singlet oxygen, which is excited by 23 kcal/mol, has all paired electrons. Thus, singlet oxygen is not a free radical, but is a reactive oxygen species.

In the metabolic process called the respiratory chain in the mitochondria present in the cytoplasm of most living cells in which oxygen is used to create energy from the carbon and hydrogen in food while also producing carbon dioxide and water, some of oxygen reactions go astray. The carbon and hydrogen atoms in food lose electrons, thus increasing their valance state (oxidation number) and are thus "oxidized." Normally, oxygen is reduced by a two-electron step. This is called a "reduction" as it reduces the valance state (oxidation number) of oxygen.

Approximately one-to-two percent of the time single-electron reactions occur creating a side reaction that produces very reactive oxygen radicals. There are several intermediate steps in this minor pathway that can reduce oxygen to water, but along the way form some potentially dangerous free radicals and other reactive oxygen species.

When an electron is added to a diatomic oxygen molecule, it creates the superoxide anion radical, which has a negative charge. Once a superoxide anion radical is formed, free radicals may be propagating through the body until there is termination – until there is another radical species that can couple and quench the superoxide. In the body, this can be accomplished by the antioxidant enzyme superoxide dismutase (SOD). SOD can take two superoxide anion radicals – therefore two free radicals – and dismute them, i. e., take an electron from one radical and add it to the other. When an electron is taken from one superoxide anion radical, it becomes diatomic oxygen again. When that electron is added to the other superoxide anion radical, it becomes a peroxide having paired electrons. This becomes hydrogen peroxide, which is a reactive oxygen species, but not a free radical. The antioxidant enzyme catalase can convert hydrogen peroxide to water, as can the family of selenium-containing enzymes called glutathione peroxidases.

If a hydrogen peroxide molecule is not reduced to water it can damage body components, but even worse, it can be reduced with the addition of another electron to a hydroxyl free radical plus a hydroxyl ion. That is, a negatively charged species and a free radical are formed. The hydroxyl free radical is an extremely reactive free radical. It can react with almost everything as fast as it collides with things. The hydroxyl radical reacts almost every time it bumps into another molecule to pull off a hydrogen atom and become water while simultaneously producing another free radical in the remainder of the other molecule.

Reactive Oxygen Species: This term Reactive Oxygen Species (ROS) includes oxygen free radicals and other oxygen species that can damage body components. ROS includes singlet oxygen (1O2) and hydrogen peroxide (H2O2).

Reactive Nitrogen Species: Reactive Nitrogen Species (RNS) include nitrogen-containing free radicals and other proxidant nitrogen-containing compounds. Nitric oxide (NO) is an example of a nitrogen free radical that is very important in the body. NO is not a very reactive free radical, but it is involved in reactions ranging from smooth muscle cell relaxation to nerve transmission of electrical impulses from one cell to the next. It hasn’t been too many years since NO was of interest mainly because it was a damaging component of smog. Its presence in the body was believed to be merely as a consequence of pollution. Now we know that when angina patients take nitroglycerine, the relief is due to the fact that NO is released which causes the muscles in the artery wall to relax, reduce blood pressure and allow more blood to flow into the heart.

The peroxynitrate radical is another nitrogen free radical that can cause considerable damage to body components.