Effects of antioxidant enzymes in the molecular control of reactive oxygen species toxicology
Introduction
Reactive Oxygen Species (ROS) are produced during normal cellular function. ROS include hydroxyl radicals (OH), superoxide anion (O2−), hydrogen peroxide (H2O2) and nitric oxide (NO). They are very transient species due to their high chemical reactivity that leads to lipid peroxidation and oxidation of some enzymes, and a massive protein oxidation and degradation (Matés et al., 1999a). The role of oxygen-derived species in causing cell injury or death is increasingly recognized: superoxide and hydroxil radicals are involved in a large number of degenerative changes, often associated with an increase in peroxidative processes and linked to low antioxidant concentration (Tamagno et al., 1998).
The prevention of lipid peroxidation is an essential process in all the aerobic organisms, as lipid peroxidation products can cause DNA damage. Increased lipid peroxidation and decreased antioxidant protection frequently occurs: epoxides may spontaneously react with nucleophilic centers in the cell and thereby covalently bind to DNA, RNA and protein (Matés and Sánchez-Jiménez, 1999). Such a reaction may lead to cytotoxicity, allergy, mutagenicity and/or carcinogenicity, depending of the properties of the epoxide in question. Moreover, oxidative events may play an important role in the mechanism of action of ether lipids, and oxidizability may contribute to cellular drug sensitivity (Wagner et al., 1998).
On the other hand, hydrogen peroxide has been implicated recently as an intracellular messenger that affects cellular processes including protein phosphorylation, transcription and apoptosis (Choi et al., 1998).
Section snippets
ROS neurotoxicity
Brain is especially susceptible to oxidative damages. In spite of the high rate of ROS production, due to high rate of oxidative metabolism and abundance of polyunsaturated fatty acids in cell membrane, brain has a relatively low antioxidant defense system. Among the different ROS scavengers, the glutathione (GSH) dependent system is of great importance. This system not only work as peroxide scavengers, but also to regulate the redox state of the cells.
Oxygen species are key participants in
Antioxidants against molecular toxicology
Antioxidants are substances that either directly or indirectly protect cells against adverse effects of xenobiotics, drugs, carcinogens and toxic radical reactions (Halliwell, 1995). Several biologically important compounds have been reported to have antioxidant functions. These include vitamin C (ascorbic acid), vitamin E (α-tocopherol), vitamin A, β-carotene, metallothionein, polyamines, melatonin, NADPH, adenosine, coenzyme Q-10, urate, ubiquinol, polyphenols, flavonoids, phytoestrogens,
Superoxide dismutase
Superoxide dismutase (EC 1.15.1.1) destroys the free radical superoxide by converting it to peroxide that can in turn be destroyed by catalase or GPX reactions. A low level of superoxide is constantly generated by aerobic respiration. The electron-transport chain of mitochondria, which is meant to escort four electrons to molecular oxygen to form water, occasionally leaks a single electron. Superoxide reduces Fe(III) to Fe(II), releasing the iron from storage sites so that it can react with
Induction and expression of other detoxifying enzymes genes
Detoxifying enzymes also including NAD(P)H:quinone oxidoreductases (NQO1 and NQO2) and glutathione S-transferases (GSTs) that catalyze metabolic detoxification of xenobiotics, drugs and carcinogens and, thus, protect the cells against redox cycling and oxidative stress. Genes encoding the various detoxifying enzymes are ubiquitiosly expressed and coordinately induced in response to antioxidants and xenobiotics (Radjendirane et al., 1997, Rushmore and Pickett, 1993). Deletion mutagenesis and
Altered signaling: In vitro cellular model for diabetic neuropathy
Diabetes mellitus is an endocrine disease characterized by the inability of the pancreas to secrete enough insulin to maintain physiological levels of blood glucose. The mechanisms underlying these pathological changes are as yet obscure, but hyperglycemia-induced neuronal damage may result from the induction of programmed cell death, or apoptosis (Phelan et al., 1997). High among the possible damaging mechanisms ranks the hyperglycemia-induced non-enzymatic modification of sugar moieties on
State of the art
ROS can be toxic at molecular level and they are important effectors in aging and lifespan determination. The specific cell types, however, in which oxidative damage acts as toxic and to limit lifespan of the whole organism have not been explicitly identified (Parkes et al., 1998). It is fully demostrated, however, that reactive oxygen metabolites are implicated in a wide range of degenerative processes including ischemic heart disease (Melov et al., 1998) as well as in the initiation and
Acknowledgements
This work was supported by Project SAF98-0153. Thanks are due to Maite Asenjo, M.D. for her valuable help in the preparation of the manuscript.
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