Elsevier

Toxicology

Volume 153, Issues 1–3, 16 November 2000, Pages 83-104
Toxicology

Effects of antioxidant enzymes in the molecular control of reactive oxygen species toxicology

https://doi.org/10.1016/S0300-483X(00)00306-1Get rights and content

Abstract

Reactive Oxygen Species (ROS) are produced during normal cellular function. ROS include hydroxyl radicals, superoxide anion, hydrogen peroxide and nitric oxide. They are very transient species due to their high chemical reactivity that leads to lipid peroxidation and oxidation of DNA and proteins. Under normal conditions, antioxidant systems of the cell minimize the perturbations caused by ROS. When ROS generation is increased to an extent that overcomes the cellular antioxidants, the result is oxidative stress. It is now clear that several biological molecules, which are involved in cell signaling and gene regulation systems are very sensitive to redox statue of the cell. Antioxidants are substances that delay or prevent the oxidation of cellular oxidizable substrates. The various antioxidants exert their effect by scavenging superoxide, or by activating of a battery of detoxifying/defensive proteins. The prevention of oxidation is an essential process in all the aerobic organisms, as decreased antioxidant protection may lead to cytotoxicity, mutagenicity and/or carcinogenicity. This article also focuses on the mechanisms by which antioxidants and xenobiotics induce the gene expression of detoxifying enzymes. On the other hand, small molecules that mimic antioxidant enzymes are becoming new tools for the treatment of many diseases.

Introduction

Reactive Oxygen Species (ROS) are produced during normal cellular function. ROS include hydroxyl radicals (radical dotOH), superoxide anion (Oradical dot2), 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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