Redox Biology and Life

The use of antioxidant supplements to quench radicals, thus preventing human disease, is often viewed as the only function of antioxidants and free radicals. In fact, antioxidants and radicals permeate much of the biochemistry of life. Scientists discuss this biochemical relationship between antioxidants and radicals using the language of the redox biology research field. Unlike the perception of the average American, those who study redox biology understand that free radicals are not all bad. But not all antioxidants are all good either. Life is a balance between the two. Antioxidants are used in biological systems to regulate the levels of free radicals, permitting them to perform useful biological functions without causing undesirable damage.4 Inevitably, some damage to critical molecules of the body does occur and thus repair systems are required to maintain cell viability. This concept will be discussed later, but first we need to define the terms oxidation and reduction.

The human body is comprised of many different cell types that are composed of many types of molecules. These molecules consist of elements made up of atoms that are joined by chemical bonds. Atoms, as you most likely remember from basic grade school science, are made up of a nucleus, neutrons, protons, and electrons. These electrons are involved in chemical reactions and bond atoms together to form a molecule. The behavior of an atom is determined by the number of electrons it gains or loses. The basis of understanding chemistry and biochemical reactions within the body relies on understanding the fact that electrons determine much, if not most, of the chemical properties of elements. In chemical reactions electrons are either shared or exchanged between atoms within molecules. Atoms and molecules can absorb or shed energy as electrons move into or from higher energy level orbits around an atoms nucleus. Atoms are stable when their highest energy level orbits contain paired electrons.

Enzymes are elegant molecules (mostly comprised of proteins) that were retained by life during evolution because of their ability to facilitate and control the orderly and efficient transfer of energy between atoms and molecules. When electrons transfer between molecules, energy is also transferred in reactions referred to as "redox reactions." When a molecule loses an electron, it is said to be oxidized. When a molecule receives an electron, it is said to be reduced. Thus gaining, losing, or sharing electrons results in molecular stability. When electrons are shared covalent bonds are formed that require energy to break. For example, breaking the bond between hydrogen atoms requires 104 kcal/mole of energy from some source. Nearly all of biochemistry involves the transfer of energy by movement of electrons in the formation or breaking of bonds between hydrogen, oxygen, nitrogen, carbon, and sulfur atoms. It can thus be realized that most of the reactions of life involve formation of atoms or groups of atoms capable of independent existence with at least one unpaired electron. Such atoms are known as "radicals." The first ever radical described in organic chemistry, the triphenylmethyl radical, was identified by Moses Gomberg in 1900 while working in Munich.5

In 1957, Denham Harman proposed the "free radical theory of aging."6 His hypothesis suggested that consequences of aging result from attacks by radicals generated primarily in the cell mitochondria during normal metabolism. Because of their unstable nature, highly reactive radicals enter into uncontrolled reactions that damage healthy cell tissue. As the damage to proteins, lipids, and nucleic acids in the body accumulates, aging effects ensue. Harman's theory was controversial at the time7 since most scientists thought that fleeting radicals were not likely to have a significant impact on the biochemistry of life. Over half a century of research would prove this notion to be naive. The first-hard evidence that free radicals could play a significant role in biology came in 1968 with the discovery of a specific enzyme, superoxide dismutases (SOD), whose function was the detoxification of the superoxide radical.8 Superoxide is a highly reactive oxygen radical formed by a single electron reduction reaction that occurs during normal cell metabolism. If it is not controlled, devastating cell damage can result. The importance of the SOD enzymes in preventing this damage is demonstrated by the fact that when the manganese SOD gene is "knocked out" or removed in experiments with mice, death will result within ten days after birth.9

Once it was established that free radicals could exist and interact with biomolecules, and that there were enzyme systems whose primary function was the "control" of radicals, Harman's theory began to gain acceptance. This concept of radical control carried with it the understanding that radicals were dangerous entities in a biological setting. It was quickly realized that free radicals could easily react with cellular substrates (or biomolecules) such as lipids, proteins, and DNA. When radical production exceeds the ability of an organism to control, prevent, or repair damage from these radicals, a condition termed "oxidative stress" arises. Damage to biomolecules from oxidation disturbs normal cell function. Since radicals are so potentially harmful to biomolecules, many scientists have hypothesized that where the existence of uncontrolled radicals has been observed, diseases are caused by reactive radical species damage and "oxidative stress."

As we saw, many free radicals come into existence as a byproduct of natural cell processes, such as oxygen metabolism or inflammation. For example, when cells use oxygen to oxidize glucose in the mitochondria to generate adenosine triphosphate (ATP) for cellular energy, free radicals are created. Various endogenous oxidases (enzymes that react with oxygen to change a biochemical substrate) can also create radicals as byproducts of their function. Examples of the very basic radical generation and sequestration reactions in biological systems are depicted in Figure 3.1.

Many internal processes, influenced by lifestyle choices, can affect radical levels. Cigarette smoking and excessive consumption of alcohol result in measurably increased levels of radicals. Exogenous sources and environmental conditions can create radicals from ionizing radiation (sun exposure, cosmic rays, medical X-rays, or industrial processes), environmental toxins, and atmospheric pollution (ozone or nitric oxide produced from motor exhaust) as well. Biological systems have evolved to control or sequester these radicals and still other systems have evolved to repair cell damage once it occurs. But before we can explore them further, some additional definitions are necessary.

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