Free Radicals and other reactive species in Disease

Secondary article
Article Contents
. Introduction

Barry Halliwell, National University of Singapore, Singapore

. Basic Definitions
. Free Radicals in Vivo – the Concept of Oxidative Stress

Free radicals can be generated in a wide variety of chemical and biological systems, including the formation of plastics, the ageing of paints, the combustion of fuels and in the human body. In living organisms, the levels of free radicals and other ‘reactive species’ are controlled by a complex web of antioxidant defences, which minimize (but do not completely prevent) oxidative damage to biomolecules.

Introduction
Free radicals can be generated in a wide variety of chemical and biological systems, including the formation of plastics, the ageing of paints, the combustion of fuels and in the human body. In living organisms, the levels of free radicals and other ‘reactive species’ are controlled by a complex web of antioxidant defences, which minimize (but do not completely prevent) oxidative damage to biomolecules. In human disease, this ‘oxidant–antioxidant’ balance is tilted in favour of the reactive species, so that oxidative damage levels increase. In some diseases, this makes a significant contribution to tissue injury, giving rise to prospects for therapeutic intervention with rationally designed antioxidant drugs.

Basic Definitions
Free radicals
In the structure of atoms and molecules, electrons usually associate in pairs, each pair moving within a defined region of space (an atomic or molecular orbital). One electron in each pair has a spin quantum number of 1 1/2, the other
2 1/2. A free radical is any species capable of independent existence (hence the term ‘free’) that contains one or more unpaired electrons, an unpaired electron being one that is alone in an orbital. The simplest free radical is an atom of the element hydrogen, with one proton and a single electron. Examples of oxygen-centred radicals (i.e. the unpaired electron is located on O) are superoxide (O2. 2 ) and hydroxyl (OH.). Thiyl radicals (RS.) are sulfurcentred radicals, trichloromethyl (CCl3.) is an example of a carbon-centred radical, and nitric oxide (NO.), is a free radical in which the unpaired electron is delocalized between two different atoms. A dot is always used to denote free radicals.

. Reactive Species and Human Disease
. Summary

Radicals can add together; for example, atomic hydrogen forms diatomic hydrogen (eqn [I]),
H. 1 H.!H2

[I]

and superoxide reacts with nitric oxide (eqn [II]).
O2.- 1 NO.!ONOO- (peroxynitrite)

[II]

In all cases, a nonradical is formed. This is usually less reactive than the parent radicals (e.g. H2 is less chemically reactive than H.) but not always. For example, ONOO 2 is more damaging to human tissues than either O2. 2 or
NO..
Most biological molecules are nonradicals. When a free radical reacts with a nonradical, a new free radical is generated. For example, OH. reacts with hydrocarbons
(including the fatty acid side-chains of membrane lipids) to abstract H. and leave behind a carbon-centred radical (eqn
[III]).
CH ‡ OH 3

‰IIIŠ

C ‡H2 O

This process can start the free radical chain reaction of lipid peroxidation. A reactive free radical such as OH. abstracts hydrogen from a fatty acid side-chain as above. The resulting carbon-centred radicals react with oxygen (eqn
[IV]).
C ‡O2 3

‰IVŠ

CÀ OÀO

peroxyl radical

Peroxyl radicals attack membrane proteins, and can also attack adjacent fatty acid side-chains (eqn [V]).
CÀOÀO ‡

CH 3

CÀOÀOH ‡

C

‰VŠ

lipid hydroperoxide

The C. radical reacts with O2 to give another peroxyl radical and the chain reaction continues. Hence, attack of a single OH. can cause oxidation of multiple fatty acid sidechains to lipid hydroperoxides. The polyunsaturated fatty acid side-chains essential to the fluidity of membranes are

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

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Free Radicals and