Post on 27-Jun-2020
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