The oxidative stressresponse system

Under the term oxidative stress come a variety of phenomena that are an unavoidable consequence of aerobic metabolism. By definition all aerobic organisms need oxygen, but at the same time they must avoid the inherently cytotoxic effects of oxygen. Toxicity of oxygen is not due to O2 itself but to reactive oxygen derivatives, generated by cellular processes. These derivatives are jointly referred to as reactive oxygen species (ROS). Several of these ROS are free radicals; that is, molecules or elements with one or more unpaired electrons in the outer orbital. The best-known ROS are the free radicals superoxide radical (O*-), hydroxyl radical (OH*), and nitric oxide radical (NO*; the lack of a paired electron is indicated by * in the chemical formula). Non-radical ROS are hydrogen peroxide (H2O2) and singlet oxygen (:O2). Molecular oxygen itself has two unpaired electrons, so strictly speaking it is also a radical, but the reactivity of O2 is limited due to the fact that the two electrons have equal spin (the so-called spin restriction). In ROS the spin restriction is lifted, which is why these forms are called activated oxygen.

ROS are produced at many places in the cell. Superoxide anion is produced abundantly in the respiratory chain of the mitochondria, the light-harvesting reactions of the choroplast, the reduction-oxidation reactions catalysed by cyto-chromes of the smooth endoplasmic reticulum, and the xanthine dehydrogenase pathway, which is involved with the degradation of purines to urate. Singlet oxygen is produced by so-called photo-sensibilization reactions, in which light energy is absorbed by molecules such as riboflavin, chlorophyll, and retinol, and transferred to molecular oxygen. Not all ROS are equally reactive. The most reactive species are hydroxyl radical and singlet oxygen, which react immediately with a suitable molecule and so inflict injury mainly on local cellular structures. H2O2 and superoxide anion are more stable and can move through the cell by diffusion; H2O2 can even pass cell membranes. The damaging effect of these ROS is mostly due to their ability to generate hydroxyl radicals. These reactions are catalysed by transition metals, such as iron and copper. For example, OH* is generated from H2O2 in the so-called Fenton reaction:

Although the concentration of free iron in the cell is very low (most iron is bound in porphyrins and ferritin and not available for the Fenton reaction), some iron is bound to low-molecular-mass chela-tors such as citrate, and this can catalyse the generation of OH* from H2O2.

In Chapter 5 we saw that ROS are implicated in aging and senescence according to the free radical theory of aging. The cellular basis for this theory is that ROS may cause damage to many macro-molecules in the cell, including proteins, DNA, and lipids. Protein damage may be caused by oxidation of free thiol (SH) groups, leading to loss of function. DNA damage may be due to thymidin dimers and strand breaks. Lipid damage is due to a process known as lipid peroxidation. This is a chain reaction in which an oxygen radical abstracts a hydrogen atom from an unsaturated bond in a fatty acid chain, which is followed by molecular rearrangement and uptake of oxygen, to form a lipid peroxyradical (LOO*), which can abstract H* from another lipid. Polyunsaturated fatty acid chains of membrane lipids are particularly sensitive to lipid peroxidation. Peroxidation causes loss of membrane flexibility, loss of activity of membrane-bound enzymatic processes, and, in the most severe form, lipid destruction followed by the appearance of volatile alkanes, alkenes, and aldehydes.

Obviously, there are great advantages in the use of oxygen gas as an electron acceptor in cellular respiration; however, damage induced by ROS is an unavoidable side effect. Protection against ROS damage is an evolutionary neccessity that must compensate the disadvantage. A great variety of antioxidant systems is deployed, using two strategies: scavenging (neutralization of ROS by reaction with a reductant) and enzymatic transformation (dismutation or reduction) to a non-reactive form. Table 6.3 provides an overview of the major

Table 6.3 Major antioxidant systems protecting the cell against injury from radical oxygen species

Antioxidant system

Primary localization


Copper- and zinc-containing

Cytosol, nucleus

Catalyses dismutation of O'T to H2O2

superoxide dismutase (Cu/Zn SOD)

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