Free Radicals i nBiology an dMedicine

FOURTH EDITIO N

Barry Halliwel l

John M .C. Gutteridge

Abbreviations

xxix

1 Oxygen is a toxic gas-an introduction to oxyge ntoxicity and reactive species

1

1 .1 The history of oxygen : an essential air pollutant

1

1 .1 .1 The paradox of photosynthesis

5

1 .1 .2 Hyperoxia in history?

5

1 .1 .3 Oxygen in solution

5

1 .2 Oxygen and anaerobes

6

1 .2.1 Why does oxygen injure anaerobes?

7

1 .3 Oxygen and aerobes

8

1 .3 .1 Oxygen transport in mammals

8

1 .3 .2 Oxygen sensing

9

1 .3 .3 Mitochondrial electron transport

9

1 .3 .4 The evolution of mitochondria

1 3

1 .3 .5 Bacteria electron transport chains

1 3

1 .4 Oxidases and oxygenases in aerobes

1 3

1 .4.1 Cytochromes P450

1 3

1 .5 Oxygen toxicity in aerobes

1 5

1 .5 .1 Bacteria and plants

1 5

1 .5 .2 Oxygen toxicity in animals

1 6

1 .5 .3 Retinopathy of prematurity and brain damage

1 8

1 .5 .4 Resuscitation of newborns

1 8

1 .5 .5 Factors affecting oxygen toxicity

1 8

1 .6 What causes the toxic effects of oxygen?

1 9

1 .7 So free radicals cause most oxygen toxicity? What then are free radicals?

1 9

1 .8 Oxygen and its radicals

2 1

1 .8.1 Singlet oxygen

22

1 .8.2 Superoxide radical

22

1 .9 Saying it correctly : oxygen radicals, oxygen-derived species,

reactive oxygen species or oxidants?

22

1 .10 Sources of superoxide in aerobes

22

1 .10.1 Enzymes

2 3

1 .10.2 Auto-oxidation reactions

23

1 .10.3 Haem proteins

23

1 .10 .4 Mitochondrial electron transport

24

1 .10.5 Mitochondrial DNA (mtDNA)

2 6

1 .10.6 Uncoupling proteins as antioxidants?

2 7

1 .10 .7 Bacterial superoxide production

2 7

1 .10 .8 Endoplasmic reticulum

2 7

1 .10.9 Other cell membranes

2 8

1 .10.10 Quantification

2 8

1 .11 Artefacts in cell culture

28

2 The chemistry of free radicals and related 'reactive species'

30

2 .1 Introduction

30

2 .2 How do radicals react?

30

2 .3 Radical chemistry : thermodynamics versus kinetics

3 1

2 .3.1 Oxidation and reduction

3 1

2 .3 .2 Reaction rates and rate constants : definitions

3 5

2 .3.3 Reaction rates and rate constants: measurements

36

2 .4 Chemistry of transition metals

3 8

2 .4 .1 Iron

3 8

2 .4 .2 Copper

4 0

2 .4 .3 Manganese

40

2 .4 .4 The Fenton reaction

4 0

2 .4 .5 Iron chelators and Fenton chemistry: speed it up or slow it down?

41

2 .4 .6 Reaction of copper ions with H2 O2

42

2.5 Chemistry of other biologically important radicals

42

2 .5 .1 Hydroxyl radical

42

2 .5 .2 Carbonate radical

45

2 .5 .3 Superoxide radical

46

2 .5 .4 Peroxyl and alkoxyl radicals

50

2 .5 .5 Sulphur radicals

52

2 .5 .6 Nitric oxide

53

2.6 Chemistry of biologically important non-radicals

60

2 .6 .1 Peroxynitrite

6 0

2.6 .2 Hydrogen peroxide

6 6

2.6 .3 Hypochlorous acid

6 8

2 .6 .4 Singlet oxygen

6 9

2.6.5 Ozone

74

3 Antioxidant defences: endogenous and diet derived

79

3 .1 Introduction

793 .1 .1 The simplest defence: avoid 02 as much as possible

79

3 .1 .2 Other antioxidant defences

79

3 .1 .3 What is an antioxidant? A new definition

80

3.2 Antioxidant defence enzymes : superoxide dismutases (SODs)

8 1

3.2.1 Copper-zinc SOD

8 1

3.2.2 Manganese SOD (sometimes called SOD2)

8 7

3 .2.3 Iron and cambialistic SODs

8 8

3 .2.4 Nickel-containing SODs

91

3 .2 .5 Assaying SOD

9 13 .2 .6 Using SOD enzymes as probes for superoxide

9 53 .2 .7 Superoxide and other metalloproteins

9 53 .3 Superoxide reductases

953 .4 Superoxide dismutases ; are they important in vivo?

963 .4 .1 Gene knockout in bacteria and yeasts

9 63 .4 .2 Transgenic animals

9 7

3 .4 .3 RNA interference

99

3 .4 .4 Induction experiments

99

3 .4 .5 SOD and oxygen toxicity in animals

99

3 .4 .6 SOD and hibernation

1003 .5 The superoxide theory of oxygen toxicity : variations and anomalies

1003 .5 .1 Anaerobes with SOD and aerobes without SOD

1003 .5.2 Manganese can replace SOD

1003 .6 Why is superoxide cytotoxic?

10 13 .6 .1 Direct damage by superoxide : not very super but

super enough?

10 13 .6 .2 Cytotoxicity of superoxide-derived species

1023 .7 Antioxidant defence enzymes : catalases

1053 .7.1 Catalase structure

1063 .7.2 The reaction mechanism of catalase

10 7

3 .7.3 Catalase inhibitors

10 8

3 .7.4 Peroxidatic activity of catalase

10 8

3 .7 .5 Photosensitization by catalase

10 8

3 .7 .6 Subcellular location of catalase

108

3 .7 .7 Manganese-containing catalases

109

3 .7 .8 Acatalasaemia

109

3.8 Antioxidant defence enzymes: the glutathione peroxidase family

11 0

3 .8 .1 A family of enzymes

11 0

3 .8 .2 The role of selenium

11 2

3 .8 .3 Glutathione reductase

11 3

3 .8 .4 Watching GPx in action

11 3

3 .9 Glutathione in metabolism and cellular redox state

11 4

3 .9 .1 Cofactor and redox agent

11 4

3 .9 .2 GSH as an antioxidant

11 5

3 .9 .3 Glutathione biosynthesis and degradation

11 5

3 .9 .4 Defects in GSH metabolism: humans and transgenic animals

11 6

3 .9 .5 The glutathione S-transferase superfamily

11 8

3 .9 .6 Mixed disulphides involving glutathione :

pathological or protective?

120

3.10 Protein-disulphide isomerase

12 1

3 .11 Thioredoxin and peroxiredoxins: key players in peroxide metabolism

122

3 .11 .1 Catalase, glutathione peroxidases and peroxiredoxins :

fitting it all together

12 3

3 .11 .2 Selenium deficiency: reinterpretation of an old paradigm

12 4

3 .12 Other sulphur-containing compounds involved i n

antioxidant defence

126

3 .12 .1 Trypanothione: an antioxidant defence in some parasites

1263 .12 .2 Ergothioneine

127

3 .13 Antioxidant defence enzymes: other peroxidases

1273.13 .1 Cytochrome c peroxidase : another specific peroxidase

1273.13 .2 NADH oxidase

1283 .13 .3 'Non-specific' peroxidases

1283 .13 .4 Horseradish peroxidase

1283 .13 .5 Why do plants have so much peroxidase?

129

3 .13 .6 Chloroperoxidase and bromoperoxidase

13 0

3.13 .7 Ascorbate peroxidase

130

3.13 .8 Peroxidase 'mimics'

130

3 .14 Antioxidant defence enzymes: co-operation

130

3.14 .1 The need for co-operation

130

3 .14 .2 Down's syndrome

13 2

3 .15 Antioxidant defence : sequestration of metal ions

132

3.15 .1 Iron metabolism

132

3.15 .2 Copper metabolism

138

3.15 .3 Haem proteins : potential pro-oxidants

139

3.15 .4 Metal ion sequestration; why do it?

140

3 .15 .5 Metal ion sequestration : when it goes wrong

141

3 .16 Metal ions and antioxidant defence: intracellular an d

extracellular strategies

144

3 .16 .1 Metallothioneins

144

3 .16 .2 Phytochelatins

145

3 .16.3 Extracellular antioxidant defence

145

3 .17 Haem oxygenase

148

3 .18 Antioxidant protection by low-molecular-mass agents :

compounds synthesized in vivo

149

3 .18.1 Bilirubin

152

3.18 .2 a-Keto acids

152

3.18 .3 Melatonin

152

3.18 .4 Lipoic acid

154

3 .18 .5 Coenzyme Q

155

3 .18 .6 Uric acid

155

3 .18.7 Histidine-containing dipeptides

157

3 .18.8 Trehalose (a-D-glucopyranosyl-1,1-a-D-glucopyranoside)

158

3 .18.9 Melanins: hair, skin, corals, fungi and fish

158

3 .19 Gender affects antioxidant defence

159

3 .20 Antioxidant protection by low-molecular-mass agents :

compounds derived from the diet

160

3.20 .1 Ascorbic acid (vitamin C)

160

3.20 .2 Vitamin E

166

3.21 Carotenoids : bright colours but not sparkling antioxidants?

174

3.21 .1 Carotenoid chemistry

175

3.21 .2 Metabolic roles of carotenoids

177

3 .21 .3 Carotenoids and vitamin A as antioxidants

177

3 .22 Plant phenols

1793 .22 .1 Phenols in the diet

18 03 .22 .2 Are plant phenols antioxidants in vivo?

18 23 .22 .3 Pro-oxidant effects of phenols?

18 43 .22 .4 Herbal medicines

18 5

4 Cellular responses to oxidative stress : adaptation, damage,repair, senescence and death

1874 .1 Introduction

1874.1 .1 Defining oxidative stress and oxidative damage

18 74 .2 Consequences of oxidative stress : proliferation, adaptation ,

senescence, damage or death?

18 84 .2 .1 Proliferation

18 84.2 .2 Adaptation

1894.2 .3 Cell injury and senescence

19 04 .2 .4 Poly(ADP-ribose)polymerase

19 14 .3 Oxidative stress causes changes in cellular ion metabolism

19 14.3 .1 Basic principles

19 14.3 .2 Calcium

19 24.3 .3 Iron

19 54.3 .4 Copper

19 84 .4 Consequences of oxidative stress : cell death

1994.4 .1 Apoptosis

1994 .5 Redox regulation

20 74.5 .1 What is it and how does it work?

20 74.5 .2 Bacterial redox regulation: oxyR

2074.5 .3 Bacterial redox regulation: soxRS

2084.5 .4 Redox regulation in yeast

2084.5 .5 Redox regulation in animals: kinases and phosphatases

2084.5 .6 Reactive species as mediators of the actions of signalling

molecules?

21 14.5 .7 Intraorganelle communication?

21 14.5 .8 NF-h:B

21 34.5 .9 AP-1

21 44.5 .10 The antioxidant response element

21 54 .5 .11 Getting it together: co-operation and combination

21 54.5 .12 Is it real? Physiological significance of redox regulatio n

in animals

21 54 .5 .13 Lessons from an amoeba

21 64 .6 Heat-shock and related 'stress-induced' proteins, cross talk with ROS

21 74.7 Cytokines, hormones and redox-regulation of the organism

21 84.7 .1 TNFr

21 94 .7.2 Interleukins

2204 .7 .3 The acute-phase response

2204.8 Mechanisms of damage to cellular targets by oxidative stress : DNA

22 04 .8.1 DNA structure

22 04 .8.2 Damage to DNA by reactive species

2224 .8.3 Damage to mitochondrial and chloroplast DNA

229

4.9 Consequences of damage to DNA by reactive species

23 04 .9 .1 Mutation

23 04 .9 .2 Misincorporation

23 24 .9 .3 Changes in gene expression

23 24 .9 .4 Having sex

23 24 .10 Repair of oxidative DNA damage

23 24 .10.1 Reversing the chemical change

2324 .10.2 Don't let it in : sanitization of the nucleotide pool

2334 .10.3 Chop it out : excision repair

2334 .10.4 Mismatch repair

2344 .10.5 Repair of 8OHdG

2344 .10 .6 Repair of double-strand breaks

235

4 .10 .7 Mitochondrial DNA repair

235

4 .10 .8 Is DNA repair important?

235

4 .10 .9 Oxidative RNA damage

236

4.11 Mechanisms of damage to cellular targets by oxidative

stress : lipid peroxidation

236

4.11 .1 A history of peroxidation : from oils and textiles to breast implants

236

4.11 .2 Targets of attack : membrane lipids and proteins

2374.11 .3 Targets of attack : dietary lipids, and lipoproteins

238

4 .11 .4 How does lipid peroxidation begin?

2384 .11 .5 Propagation of lipid peroxidation

242

4 .11 .6 Transition metals and lipid peroxidation

243

4 .11 .7 Microsomal lipid peroxidation

247

4 .11 .8 Acceleration of lipid peroxidation by species other tha n

oxygen radicals

248

4 .12 Lipid peroxidation products: bad, good or indifferent?

249

4 .12 .1 General effects

249

4 .12.2 Lipid hydroperoxides (ROOH)

249

4 .12.3 Isoprostanes, isoketals and cyclopentenone compounds

250

4 .12 .4 Cholesterol oxidation products (COPs)

253

4 .12 .5 Decomposition products from lipid peroxides : what do they do?

253

4 .12 .6 Peroxidation of other molecules

258

4 .12 .7 Repair of lipid peroxidation

258

4.12 .8 Lipids as antioxidants? The plasmalogens

25 9

4.12 .9 Polyamines: antioxidants or pro-oxidants?

260

4.13 Mechanisms of damage to cellular targets by oxidative stress :protein damage

260

4.13 .1 Does protein damage matter?

260

4.13 .2 How does damage occur? Is it random or specific?

261

4.13 .3 Chemistry of protein damage

26 1

4.13 .4 Damage to specific amino-acid residues

264

4 .14 Dealing with oxidative protein damage

26 4

4 .14 .1 Repair of methionine residues

264

4 .14 .2 Removal : lysosomes and proteasomes

26 5

4 .15 Summary: oxidative stress and cell injury

267

5 Measurement of reactive species

26 8

5 .1 Introduction

268

5 .1 .1 Trapping

268

5 .1 .2 Fingerprinting: the biomarker concept

268

5 .1 .3 Indirect approaches

26 95 .2 ESR and spin trapping

270

5 .2.1 What is ESR?

270

5 .2 .2 Measurement of oxygen

272

5 .2 .3 Spin trapping

272

5 .2 .4 DMPO, DEPMPO and PBN

2735 .2 .5 Ex vivo trapping in humans

2755 .2 .6 Further cautions in the use of spin traps

2765.2 .7 Trapping thiyl radicals

277

5 .2 .8 Spin-trapping without ESR?

277

5 .3 Other trapping methods, as exemplified by hydroxyl-radical trapping

278

5.3 .1 Aromatic hydroxylation

278

5 .3 .2 Use of hydroxyl-radical scavengers

28 1

5 .3 .3 The deoxyribose assay

28 1

5 .3 .4 Measurement of rate constants for OH ' reactions

28 1

5 .3 .5 Other trapping methods for hydroxyl radical

28 2

5 .4 Detection of superoxide

28 2

5 .4 .1 The aconitase assay

28 5

5 .4 .2 Rate constants for reactions with 0z-

28 5

5 .4 .3 Triphenyl radical-based probes

286

5 .4 .4 Histochemical detection

286

5 .5 Detection of nitric oxide

286

5 .5 .1 Calibration

286

5.6 Detection of peroxynitrite and other reactive nitrogen species

286

5 .6 .1 Probes for peroxynitrite

286

5 .6 .2 Nitration assays

292

5.7 Detection of reactive halogen species

293

5.8 Detection of hydrogen peroxide

295

5.9 Detection of singlet oxygen

296

5 .9 .1 Direct detection

30 1

5 .9 .2 Use of scavengers and traps

30 1

5 .9.3 Deuterium oxide (D2O)

302

5 .10 Studies of 'generalized' light emission (luminescence/fluorescence)

302

5 .11 Measurement of reactive species in cultured cells

302

5 .11 .1 Dichlorofluorescin diacetate (DCFDA)

304

5 .11 .2 Dihydrorhodamine 123 (DHR)

30 5

5 .11 .3 Dihydroethidium

30 5

5 .11 .4 Luminol and lucigenin

30 5

5 .11 .5 Alternative fluorescent probes for superoxide

30 7

5 .11 .6 Measuring the light output of fluorescent probes

30 7

5 .11 .7 Effects of reactive species on other probes

308

5 .12 Biomarkers: the promise of urate oxidation?

308

5 .13 Biomarkers of oxidative DNA damage

309

5 .I3 .1 Characterizing DNA damage: why bother to do it?

309

5 .13 .2 Characterizing DNA damage: what to measure?

30 9

5 .13 .3 Characterizing DNA damage: how to measure it

31 1

5 .13 .4 Steady-state damage : the artefact problem

31 2

5 .13 .5 Overcoming the artefact

31 35 .13 .6 Interpreting the results : measure DNA levels or urinary

excretion? What do the levels mean?

314

5 .13 .7 Reactive nitrogen and chlorine species

31 5

5 .13 .8 Gene-specific oxidative damage

31 6

5 .13 .9 DNA-aldehyde adducts

31 6

5.14 Biomarkers of lipid peroxidation

31 6

5 .14 .1 Why measure lipid peroxidation?

31 7

5 .14 .2 How to measure lipid peroxidation : general principles

31 7

5 .14 .3 Loss of substrates

31 7

5 .14 .4 Measurement of intermediates

31 8

5 .14 .5 Measurement of end-products : peroxides

31 9

5 .14 .6 Measurement of end products: isoprostanes, isofurans and isoketals 319

5 .14 .7 Measurement of end products : aldehydes

322

5 .14.8 Measurement of end products : breath analysis

325

5 .14 .9 The TBA assay (thiobarbituric acid or 'that bloody assay')

326

5 .14 .10 Measuring lipid peroxidation : light emission

329

5 .14.11 A summary: what is the best method to measure lipid

peroxidation in tissues, cells and body fluids?

329

5 .14.12 Visualizing lipid peroxidation

330

5 .14.13 Probes of lipid peroxidation/ membrane reactive species

330

5 .15 Biomarkers of protein damage by reactive species

333

5 .15 .1 Damage by reactive oxygen species

333

5 .15 .2 Damage by reactive halogen and nitrogen species

333

5 .15 .3 The carbonyl assay

336

5 .16 Is there a single biomarker of oxidative stress or oxidative damage?

336

5 .17 Assays of total antioxidant capacity

33 7

5 .17 .1 What do changes in total antioxidant capacity mean?

33 7

6 Reactive species can pose special problems needin gspecial solutions : some examples

34 1

6.1 Introduction

34 1

6 .2 The gastrointestinal tract

34 1

6 .2 .1 Threatening your guts

34 1

6 .2 .2 Defending your guts

342

6 .3 The respiratory tract

344

6.3 .1 The challenges

344

6 .3 .2 Defending the respiratory tract

345

6 .3 .3 Asthma and antioxidants

34 6

6 .4 Erythrocytes

346

6 .4 .1 What problems do erythrocytes face?

346

6 .4 .2 Solutions : antioxidant defences

34 7

6 .4 .3 Solutions : diet-derived antioxidants

349

6 .4 .4 Erythrocyte peroxidation in health and disease

349

6 .4.5 Glucose-6-phosphate dehydrogenase (G6PDH) deficiency

35 06 .4.6 Solutions : destruction

35 06 .5 Erythrocytes as targets for toxins

35 06 .5 .1 Hydrazines

35 06 .5 .2 Sulphur-containing haemolytic drugs

35 36 .5 .3 Favism

35 36 .6 Bloodthirsty parasites : problems for them and for us

35 36 .6 .1 Malaria, oxidative stress and an ancient Chinese herb

35 4

6 .7 Oxidation in plants : peroxides and phytoprostanes

35 66 .7 .1 Sources of ROS in plants

35 6

6 .8 The origins of life: chloroplasts

35 6

6 .8 .1 Structure and genetics

35 6

6.8 .2 Trapping of light energy

35 7

6 .8 .3 The water splitting mechanism : a radical process and

the reason for this book

36 0

6 .8 .4 What problems do green leaves face?

36 1

6 .8 .5 Solutions : minimizing the problem

36 3

6 .8 .6 The xanthophyll cycle

364

6 .8 .7 Solutions : antioxidant defence enzymes control, but do no t

eliminate, reactive species

365

6 .8 .8 Ascorbate and glutathione

366

6 .8 .9 Plant tocopherols

367

6 .8.10 Solutions: repair and replacement

3676 .8.11 The special case of the root nodule

3686 .9 Plants as targets for stress and toxins

3686 .9 .1 Inhibition of electron transport and carotenoid synthesis

3686 .9.2 Bipyridyl herbicides

368

6.9 .3 Environmental stress : air pollutants (ozone, sulphur dioxide ,

nitrogen dioxide)

371

6.9 .4 Environmental stress: heat and cold

37 1

6.9 .5 Coral reef bleaching and toxic algal blooms : examples o f

plant-dependent oxidative stress?

373

6 .10 The eye

37 3

6 .10 .1 What problems does the eye face?

37 3

6.10.2 Solutions

37 7

6.10.3 Toxins, inflammation and the eye

379

6.10.4 The thorny question of ocular carotenoids : a Chinese herb

good for the eyes?

379

6 .10 .5 Antioxidants, cataract and macular degeneration

379

6 .11 Reproduction and oxidative stress

38 0

6 .11 .1 Preconception: spermatozoa have problems

380

6 .11 .2 The female story

38 16 .11 .3 Spermatozoa : the solutions

38 16 .11 .4 Spermatozoa as targets for toxins

38 16 .11 .5 Problems of the embryo

3826 .11 .6 Problems of pregnancy: normal and abnormal 02

3826 .11 .7 The embryo/ foetus as a target for toxins

3846 .11 .8 Birth

385

6 .12 The skin

38 7

6 .12 .1 Problems of the skin

38 8

6 .12 .2 The solutions

39 06 .12 .3 Wounds and burns

39 1

6 .13 Exercise: a cause of or a protection against oxidative stress?

392

6 .13 .1 Exercise, lack of exercise and oxidative damage

392

6 .13 .2 Exercise, health and free radicals

393

6 .13 .3 Muscle as a target for toxins

394

7 Reactive species can be useful : some more examples

395

7 .1 Introduction

395

7 .2 Radical enzymes: ribonucleotide reductase and its colleagues

395

7 .2 .1 The enzyme mechanism

39 5

7 .2.2 Inhibitors of RNRs

396

7 .2 .3 Class III ribonucleotide reductases and other 'sons of SAM' enzymes

39 7

7 .2 .4 Class II ribonucleotide reductases and other cobalamin

radical enzymes

39 7

7.3 Pyruvate-formate lyase: a similar mechanism

39 7

7 .3 .1 Pyruvate-ferredoxin oxidoreductase

398

7.4 Assorted oxidases

39 8

7 .4 .1 Galactose oxidase

398

7 .4 .2 Indoleamine dioxygenase

399

7.5 Useful peroxidases

399

7.5 .1 Thyroid hormone synthesis

399

7 .5 .2 An 'antimolestation' spray

40 1

7.5 .3 Thick coats

40 1

7.5 .4 Making and degrading lignin

40 1

7 .6 Light production

403

7.6 .1 Green fluorescent protein: another example of autocatalytic oxidation

403

7 .7 Phagocytosis

405

7.7.1 Phagocyte recruitment, adhesion, activation and disappearance

40 7

7.7.2 How do phagocytes kill?

412

7.7.3 The enigma of myeloperoxidase

41 7

7 .8 Other phagocytes: similar but different

420

7 .9 What do phagocyte-derived reactive species do to the host?

42 17.9 .1 Extracellular RS: what can they do?

42 1

7 .9.2 Signalling

4227 .9 .3 Damage to the phagocyte

4227 .9.4 Damage by phagocytes can be severe : the tragedy of

chronic inflammation

423

7 .9.5 What does it all mean? Are RS both pro- and anti-inflammatory?

424

7 .9.6 Defeating the system: bacterial and fungal avoidance strategies

424

7 .10 NAD(P)H oxidases in other cell types

425

7 .10 .1 The gastrointestinal tract

42 6

7 .10 .2 C. elegans

426

7 .10 .3 Blood vessel walls

42 6

7 .10 .4 Lymphocytes

42 7

7 .10 .5 Reactive species, renal function and oxygen sensing

427

7 .10 .6 Platelets

42 87 .10 .7 Osteoclasts

42 87 .10 .8 Other redox systems

42 87.11 Even plants use reactive species

42 87 .11 .1 The hypersensitive response

42 97 .11 .2 Germination and senescence

43 07 .11 .3 Plant lipoxygenases

43 1

7 .11 .4 The injury response and oxylipid signalling

43 17.12 Animal lipoxygenases and cyclooxygenases : stereospecifi c

lipid peroxidation

43 27 .12 .1 Eicosanoids : prostaglandins and leukotrienes

43 27 .12 .2 Prostaglandins and thromboxanes

4337 .12 .3 Prostaglandin synthesis

43 47 .12 .4 Regulation by 'peroxide tone'

43 47 .12 .5 Prostaglandins from isoprostanes? Cross-talk of the systems

43 67 .12 .6 Levuglandins

4367 .12 .7 Prostacyclins and thromboxanes

43 67 .12 .8 Leukotrienes and other lipoxygenases products

43 8

8 Reactive species can be poisonous : their role in toxicology

440

8 .1 Introduction

44 0

8 .1 .1 What is toxicology?

44 0

8 .1 .2 Principles of toxin metabolism

44 0

8 .1 .3 How can reactive species contribute to toxicity?

44 1

8 .2 Carbon tetrachloride

44 2

8 .2 .1 Carbon tetrachloride synthesis : a free-radical chain reaction

442

8 .2 .2 Toxicity of CC1 4

444

8 .2.3 How does CC1 4 cause damage?

444

8 .3 Other halogenated hydrocarbons

445

8 .3 .1 Chloroform and bromotrichloromethane

4468 .3 .2 Pentachlorophenol and related environmental pollutants

4468 .4 Redox-cycling toxins : bipyridyl herbicides

44 7

8 .4.1 Toxicity to bacteria

447

8 .4 .2 Toxicity to animals

447

8 .4 .3 Why is paraquat toxic to the lung?

448

8 .5 Diabetogenic drugs

449

8 .5 .1 Alloxan

449

8 .5 .2 Streptozotocin

45 1

8 .6 Redox-cycling toxins : diphenols and quinones

45 1

8 .6 .1 Interaction with 0 2 and superoxide

45 1

8 .6.2 Interaction with metals

45 1

8 .6.3 Mechanisms of toxicity

45 3

8.6 .4 Quinone reductase

45 3

8.6 .5 Catechol oestrogens

45 4

8.6 .6 Substituted dihydroxyphenylalanines and 'manganese madness'

45 4

8 .6 .7 Neurotoxicity of 6-hydroxydopamine

455

8.6 .8 Benzene and its derivatives

4568.6 .9 Toxic-oil syndrome and a new society

456

8 .7 Redox-cycling agents: toxins derived from Pseudomonas aeruginosa

45 78 .8 Alcohols

45 78 .8 .1 Ethanol

45 7

8 .8 .2 Allyl alcohol and acrolein

46 1

8 .9 Other recreational drugs

46 1

8 .10 Paracetamol (acetaminophen), a glutathione-depleting toxin

46 1

8 .11 Air pollutants

46 38 .11 .1 Ozone, a non-radical reactive species

46 4

8 .11 .2 Nitrogen dioxide

464

8 .11 .3 Sulphur dioxide

466

8 .12 Toxicity of mixtures : cigarette smoke and other 'toxic smokes'

46 7

8 .12 .1 Chemistry of tobacco smoke

46 7

8 .12.2 Mechanisms of damage by cigarette smoke

469

8 .12.3 How does the respiratory tract defend itself?

470

8 .12 .4 Adaptation

470

8 .12.5 Environmental tobacco smoke (ETS)

47 1

8 .12.6 Other tobacco usage

47 1

8 .12.7 Fire smoke

47 1

8 .13 Diesel exhaust

47 1

8 .14 Toxicity of asbestos and similar particulates

472

8 .15 Toxicity of metals

472

8 .15 .1 Cause or consequence?

472

8 .15 .2 Arsenic

473

8 .15.3 Nickel

474

8 .15.4 Chromium

474

8 .15 .5 Cobalt

475

8 .15.6 Cadmium

475

8 .15 .7 Mercury

475

8 .15 .8 Lead

476

8 .15.9 Vanadium

476

8 .15 .10 Titanium

477

8 .15 .11 Aluminium

477

8 .15.12 Zinc

478

8 .16 Antibiotics

478

8 .16.1 Tetracyclines as pro- and antioxidants

478

8 .16.2 Quinone antibiotics

480

8 .16.3 Aminoglycoside nephrotoxicity and ototoxicity

481

8 .17 Noise and stress

481

8 .18 Nitro and azo compounds

482

8 .18.1 Nitro radicals and redox cycling

482

8 .18.2 Further reduction of nitro radicals

48 2

8 .18.3 Azo compounds

484

8 .19 Ionizing radiation

48 4

8 .19.1 The oxygen effect

484

8 .19.2 Antioxidants and radiotherapy

48 5

8 .19.3 Hypoxic-cell sensitizers

48 6

8 .19.4 Food irradiation

48 6

8 .20 Summary and conclusion

486

9 Reactive species and disease : fact, fiction or filibuster?

4889 .1 Setting the scene

48 89 .2 Does oxidative stress matter?

48 89 .2.1 Establishing importance

49 19 .3 Atherosclerosis

49 49 .3 .1 What is atherosclerosis?

49 49 .3 .2 Predictors of atherosclerosis

49 69 .3 .3 What initiates atherosclerosis?

49 79.3 .4 LDL oxidation and the foam cell

49 79.3 .5 Mechanisms of LDL oxidation

49 99.3 .6 Other aspects of the involvement of RS in atherosclerosis

50 19.3 .7 Does evidence support the 'oxidative modification hypothesis '

of atherosclerosis?

50 19 .3 .8 Chemistry of LDL oxidation: is in vitro LDL oxidation a

relevant model?

50 29 .3 .9 The role of high-density lipoproteins

50 79 .3 .10 Lipoprotein (a)

50 89 .3 .11 Unanswered questions

5089 .4 Diabetes

5089 .4 .1 Can oxidative stress cause diabetes?

5099 .4 .2 Oxidative stress in diabetic patients

5099 .4 .3 How does the oxidative stress originate?

51 09 .4 .4 Non-enzymatic glycation and glycoxidation

51 09 .4 .5 Other mechanisms of glucose toxicity : aldose reductase

51 39 .4 .6 How important is oxidative stress in diabetes?

51 49 .5 Ischaemia-reperfusion

51 49 .5.1 Reoxygenation injury

51 59 .5.2 A role for xanthine oxidase?

51 69 .5.3 Intestinal ischaemia-reoxygenation

51 69 .5 .4 Cardiac ischaemia-reoxygenation

51 79 .5 .5 Angioplasty, restenosis and bypass grafting

52 19 .5 .6 Ischaemic preconditioning

52 19 .5 .7 Shock-related ischaemia-reoxygenation

52 29 .5.8 The eye

52 29.5 .9 Plants

52 3

9.5 .10 Chemical ischaemia-reperfusion : carbon monoxide poisoning

52 3

9 .5 .11 Freezing injury

52 39.5 .12 Sleep apnoea

52 39 .6 Organ preservation, transplantation and reattachment of severed tissues

52 49.6 .1 Heart and kidney

52 49.6 .2 Liver

52 49.6 .3 Limbs, digits and sex organs

52 59 .6 .4 Organ preservation fluids

5259 .6 .5 Other examples

5269 .7 Lung damage, shock and ARDS

5269.7 .1 Oxidative stress in ARDS : does it occur and does it matter?

52 79 .8 Cystic fibrosis

52 79 .8 .1 Cystic fibrosis and carotenoids

529

9 .9 Chronic inflammatory diseases: more examples

5309 .9 .1 Are RS important mediators of autoimmune diseases?

53 19 .10 Rheumatoid arthritis

5329 .10 .1 The normal joint

5329 .10 .2 The RA joint

5339 .10 .3 Does increased oxidative damage occur in RA?

5359 .10 .4 What is the origin of the oxidative stress?

5359 .10 .5 Does oxidative damage matter in RA?

5369 .10 .6 Drugs for the treatment of RA : antioxidant, pro-oxidant or neither?

5369 .10 .7 Iron and rheumatoid arthritis

5409 .11 Inflammatory bowel disease

5409 .11 .1 The salazines

5419 .12 Inflammation of other parts of the gastrointestinal tract

5419 .12 .1 Pancreas

5419 .12 .2 Oesophagus and stomach

5429 .12 .3 Liver

5429 .13 Oxidative stress and cancer : a complex relationship

5439 .13 .1 The cell cycle

5439 .13 .2 Tumours

5449 .13 .3 Carcinogenesis

5449 .13 .4 Genes and cancer

54 79 .13 .5 Reactive species and carcinogenesis

55 09 .13 .6 Chronic inflammation and cancer : a close link but is

it due to RS?

55 49 .13 .7 Changes in antioxidant defences in cancer

55 59 .13 .8 Transition metals and cancer

55 69 .14 Carcinogens: oxygen and others

55 79 .14 .1 Carcinogen metabolism

55 79 .14 .2 Carcinogens and oxidative DNA damage

56 19 .14 .3 Reactive nitrogen species and cancer

56 49.15 Cancer chemotherapy

56 49 .15 .1 Oxidative stress and chemotherapy

56 49.15 .2 The anthracyclines and other quinones

56 6

9 .15 .3 Bleomycin

56 9

9 .15 .4 Should cancer patients consume antioxidants?

57 09.16 Oxidative stress and disorders of the nervous system : setting the scene

571

9.16 .1 Introduction to the brain

571

9.16 .2 Energy metabolism

5729.16 .3 Glutamate, calcium and nitric oxide

5749.16 .4 Excitotoxicity

57 5

9 .16 .5 Why should the brain be prone to oxidative stress?

57 6

9 .16 .6 Antioxidant defences in the brain

578

9 .17 Oxidative stress in brain ischaemia, inflammation and trauma

582

9 .17.1 Inflammation: a common feature

582

9 .17 .2 Multiple sclerosis

58 2

9 .17.3 Brain ischaemia

582

9 .17.4 Traumatic injury

586

9 .18 Oxidative stress and neurodegenerative diseases : somegeneral concepts

586

9 .19 Parkinson's disease

590

9 .19.1 Genetics or environment?

590

9 .19 .2 Treatment

59 1

9 .19 .3 Toxins and PD

592

9 .19 .4 Oxidative stress and mitochondrial defects in PD

595

9 .19 .5 What does it all mean?

5969 .20 Alzheimer's disease

5979 .20 .1 Definition and pathology

5979 .20 .2 Genetics of AD

5999 .20 .3 Mechanisms of neurodegeneration

600

9 .20 .4 Cause or consequence?

60 1

9 .20 .5 An old red herring : aluminium in AD

6039 .20 .6 Other amyloid diseases

603

9 .21 Amyotrophic lateral sclerosis (ALS)

603

9 .21 .1 Familial ALS (FALS) and superoxide dismutase

604

9 .21 .2 Oxidative damage and excitotoxicity in ALS

605

9 .22 Other neudegenerative diseases

606

9 .22 .1 Friedreich's ataxia

606

9 .22 .2 Huntington's disease

606

9 .22 .3 Prion diseases

607

9 .22 .4 Neuronal ceroid lipfuscinoses

60 89 .22 .5 Tardive dyskinesia

60 99 .22 .6 Cycads, flying foxes, guam and lathyrism : now all history?

60 9

9.23 Oxidative stress and viral infections

609

9 .23 .1 Reactive species, antioxidants and HIV

61 1

9 .23 .2 Redox regulation of viral expression

61 1

9 .23.3 Side-effects of therapy

61 3

9.24 Conclusion

61 3

10 Ageing, nutrition, disease and therapy : a role for antioxidants?

614

10 .1 Introduction

61 4

10 .2 An introduction to theories of ageing

61 4

10 .2.1 General principles

61 4

10 .2.2 What features of ageing must theories explain?

61 5

10 .3 What theories of ageing exist?

61 6

10 .3.1 Do genes influence ageing? The story of C. elegans

61 6

10 .3.2 Genes and human longevity

620

10 .3.3 Premature human ageing

62 1

10 .3.4 Mechanisms of caloric restriction

622

10 .3.5 Telomeres and cellular senescence

623

10 .4 Oxidative damage: a common link between all the theories of aging?

624

10 .4 .1 Introduction to the free radical theory of ageing

624

10 .4 .2 Testing the theory: altering antioxidant levels

62 7

10.4 .3 'Rapidly-ageing' mice

62 9

10.4 .4 Does antioxidant protection fail with age?

629

10.4 .5 Does oxidative damage increase with age?

629

10.4 .6 Lipofuscin and ceroid ; fluorescent 'red herrings'?

630

10.4 .7 Oxidative stress, oxidative damage and signal transduction

63 1

10 .4.8 The oxidative damage theory of ageing: summing it up

63 1

10 .5 Nutrition, health and oxidative damage

632

10.5 .1 Learning from epidemiology

632

10 .5 .2 Epidemiology and antioxidants

634

10.5 .3 Problems of interpretation

636

10 .5.4 The gold standard of intervention trials: hope unfulfilled

640

10 .5.5 The need for biomarkers

640

10 .5.6 Some intervention trials : a state of CHAOS

64 1

10 .5 .7 Some rays of hope and a gender bias

643

10 .5 .8 Lycopene, other carotenoids and human disease

643

10 .5 .9 Other dietary factors and oxidative damage

643

10 .5 .10 Iron, ageing and disease: another gender gap

645

10 .5 .11 Antioxidants, epidemiology and neurodegenerative disease

645

10 .5 .12 What does it all mean? Some dietary advice

646

10 .6 Antioxidants and the treatment of disease

646

10 .6 .1 Therapeutic antioxidants

647

10 .6 .2 Approaches to antioxidant characterization

647

10 .6 .3 Superoxide dismutases and catalases

648

10.6 .4 SOD/catalase mimetics

650

10 .6 .5 Spin traps/nitroxides

653

10 .6 .6 Vitamins C and E and their derivatives

658

10.6.7 Other chain-breaking antioxidants

665

10.6 .8 The lazaroids

665

10 .6.9 Thiol compounds

666

10.6.10 Glutathione peroxidase 'mimetics'

668

10.6.11 Mitochondrially-targeted antioxidants

668

10 .7 Iron chelators

669

10 .7.1 Desferrioxamine

669

10 .7.2 Other iron-chelating agents

675

10 .8 Inhibitors of the generation of reactive species

676

10 .8 .1 Xanthine oxidase (XO) inhibitors

67610 .8 .2 Inhibitors of phagocyte RS generation

677

Appendix : Some basic chemistry

678

Al Atomic structure

678

A2 Bonding between atoms

681

A2.1 Ionic bonding

681

A2.2 Covalent bonding

684

A2.3 Non-ideal character of bonds

685

A2.4 Hydrocarbons and electron delocalization

686

A3 Moles and molarity

687

A4 pH and pKa

687

References

689

Index

777