Free radicals

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Chapter 7 Free radicals

Free radicals are talked about a great deal in the realms of nutrition but very few practitioners understand exactly what they are.

How are Free Radicals Formed?

Electrons like to exist in pairs, so when atoms are chemically separated from their covalent bonds (see Chapter 3 ‘Bonds found in biological chemistry’ p. 13) they do not normally split to leave a single unpaired electron. When this does happen, a free radical is formed.

Free radicals are very unstable due to the single unpaired electron, so they are very keen to ‘steal’ an electron from the nearest stable (non-radical) molecule to gain stability. Free radicals can be formed by:

• The loss of a single electron from a normal molecule (non-radical).

• The gain of a single electron by a normal molecule (non-radical).

The ‘attacked’ molecule loses its electron and in turn becomes a free radical. This occurs quickly – in much less than a second – and the process rapidly starts a chain reaction that, once started, can cascade and ultimately result in the disruption of a cell.

What Causes Free Radicals?

• Chemicals: gases responsible for pollution, herbicides, alcohol, carcinogenic chemicals such as benzene.

• Cigarettes: fresh cigarette smoke contains high concentrations of nitric oxide, which reacts with oxygen to form nitrogen dioxide. This is a free radical and is capable of attacking unsaturated lipids at the double bonds.

• Radiation: UV light, X-rays and radioactive material. When exposed to high-intensity visible light, cells in culture are damaged, particularly the mitochondria, which are rich in the protein haem and in flavin co-containing proteins (see Chapter 13 ‘Vitamins and minerals’, p. 93). This is what happens to skin when someone is exposed to excessive UV light.

How do Free Radicals Cause Damage?

Free radicals cause damage in four ways:

1. Damage to lipids: cell membranes and organelles (e.g. mitochondria) are largely composed of lipids. When they incur damage from free radicals their function becomes impaired.

2. Damage to proteins: free radicals attack the amino acids that are the building blocks of protein structures.

3. Damage to genetic material: free radicals attack the nucleic acids (RNA and DNA), thus affecting the function, growth and repair of cells dependent on proper protein function. This is the first step in the development of cancer.

4. Lysosome destruction: lysosomes are small, enzyme-containing lipid-membrane sacs. When the lysosome is destroyed, the enzymes are released and the cell effectively digests itself. The destructive effect of the enzymes is passed to adjacent cells and creates a widespread effect.

Normal Occurrences of Free Radicals

The body needs free radicals for certain functions:

• Phase I of the liver detoxification system (see Chapter 17 ‘Metabolism’, p. 129) is necessary if other reactions are to take place under the appropriate control. The phase I pathway in the liver involves cytochrome p450 and produces free radicals as a necessary intermediary product. The phase II pathway – the conjugation pathway – adds chemical groups to the free radicals, terminating (quenching) them and returning them to normal (non-radical) molecules. If phase I is upregulated (made to work more efficiently) but phase II does not have the capacity to match this increased production of free radicals, the patient will become ill.

• The free radical hydrogen peroxide is required for the synthesis of the hormone thyroxine by the thyroid gland.

• Macrophages and neutrophils generate free radicals to kill off the bacteria they engulf by phagocytosis.

• Nitric oxide (a free radical) is now thought to be an important part of vasodilatation and neurotransmission.

• Oxidative phosphorylation: a series of free radical electron carriers in the mitochondria is responsible for energy production (see Figure 2.5, p. 10).

In a healthy individual, the free radicals that are formed by the body are dealt with via a variety of radical ‘quenching’ systems. However, if too many free radicals form then there is a problem.

Reactive Oxygen Species

Oxygen is vital to life. Ultimately, it is responsible for producing energy in living organisms, although plants are also able to use carbon dioxide for this purpose. Oxygen is an interesting molecule because in its unexcited or ‘ground state’ it has two unpaired electrons, in separate orbitals.

When an oxygen molecule interacts with other molecules to form a covalent bond, it needs to accept two electrons that are spinning in the opposite direction to its own electrons in the outermost orbital or they will not fit (it would be rather like trying to put two like poles of a magnet together, which results in repulsion). In the presence of energy, one of the electrons can change its direction of spin and pairs up with the other one to create singlet oxygen (activated oxygen) (Figure 7.1). This is not as stable as the ground state oxygen and will change back fairly quickly (less than 0.04 microseconds) but in that time it will have affected its surrounding environment.

Figure 7.1 The distribution and spin direction of all the electrons of atmospheric oxygen (O₂) in its ground state and excited (singlet) state.

Singlet oxygen is not a free radical but it can be formed during some free radical reactions and can trigger the formation of free radicals. Singlet oxygen can be formed by macrophages during phagocytosis and by light (in chlorophyll).

Singlet oxygen interacts with other molecules in two ways:

• It combines with them chemically.

• It transfers its excitation energy to them. The oxygen then returns to the ground state whereas the molecule the oxygen has interacted with becomes excited.

Thus, oxygen is activated by two different mechanisms.

• Absorbing energy: electrons orbit but, like the earth around the sun, they also spin in a particular direction. If enough energy is absorbed by the oxygen molecule then the spin of one of the orbiting electrons can be reversed (in the case of singlet oxygen the spin is reversed and the electron paired temporarily). This change activates oxygen. The oxygen will now react with organic molecules in a way it could not before it had been activated.

• Gaining an additional electron: oxygen can gain an extra electron (i.e. it is reduced) to form something called a superoxide, which in turn produces hydrogen peroxide. Hydrogen peroxide is not a free radical because its electrons are paired (Figures 7.2 and 7.3), but it can go on to produce problematic metabolic products. Its potential for damage is compounded by the fact that hydrogen peroxide easily passes through cell membranes and can therefore easily move out of the cell in which is was formed. This mobility means that it can spread around the body easily.

Figure 7.2 The formation of a free radical with oxygen.

Figure 7.3 Electron configuration of the superoxide radical and peroxide ion. Note theunpaired electron of the superoxide radical and the two sets of paired electrons of theperoxide ion (which means it is not a radical).

The products of reduced oxygen are activated products but are not free radicals, only the oxygen can be said to be a free radical (because it has two unpaired electrons it is called biradical).

Superoxides

The most important source of the superoxide radical is the electron transport chains in the mitochondria and endoplasmic reticulum (where the cytochrome P450 is stored and works in the liver). The electrons should pass from one component of these chains to another, but the relay system is not perfect and there is thought to be some ‘leakage’.

Effects of Free Radical Damage

• Cancer: damage to the DNA causes mutations that affect the normal function of the cell, eventually leading to malignancy.

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