Handbook of Antioxidants (Oxidative Stress and Disease)

731 Pages·2001·3.97 MB·English

by  Enrique Cadenas

ISBN: 0-8247-0547-5
This book is printed on acid-free paper.
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ii
Series Introduction
Oxygen is a dangerous friend. Overwhelming evidence indicates that oxidative stress can lead
to cell and tissue injury. However, the same free radicals that are generated during oxidative
stressareproducedduringnormalmetabolismandthusareinvolvedinbothhumanhealthand
disease.
Freeradicalsaremoleculeswithanoddnumberofelectrons.Theodd,orunpaired,electron
is highly reactive as it seeks to pair with another free electron.
Freeradicalsaregeneratedduringoxidativemetabolismandenergyproductioninthebody.
Free radicals are involved in:
Enzyme-catalyzed reactions
Electron transport in mitochondria
Signal transduction and gene expression
Activation of nuclear transcription factors
Oxidative damage to molecules, cells, and tissues
Antimicrobial action of neutrophils and macrophages
Aging and disease
Normal metabolism is dependent on oxygen, a free radical. Through evolution, oxygen
was chosen as the terminal electron acceptor for respiration. The two unpaired electrons of
oxygen spin in the same direction; thus, oxygen is a biradical, but not a very dangerous free
radical. Other oxygen-derived free radical species, such as superoxide or hydroxyl radicals,
formed during metabolism or by ionizing radiation are stronger oxidants and are therefore
more dangerous.
In addition to research on the biological effects of these reactive oxygen species, research
on reactive nitrogen species has been gathering momentum. NO, or nitrogen monoxide (nitric
oxide), is a free radical generated by NO synthase (NOS). This enzyme modulates physiolog-
ical responses such as vasodilation or signaling in the brain. However, during inflammation,
synthesisofNOS(iNOS)isinduced.ThisiNOScanresultintheoverproductionofNO,caus-
ing damage. More worrisome, however, is the fact that excess NO can react with superoxide
to produce the very toxic product peroxynitrite. Oxidation of lipids, proteins, and DNA can
result, thereby increasing the likelihood of tissue injury.
iii
iv Series Introduction
Bothreactiveoxygenandnitrogenspeciesareinvolvedinnormalcellregulation,inwhich
oxidants and redox status are important in signal transduction. Oxidative stress is increasingly
seen as a major upstream component in the signaling cascade involved in inflammatory re-
sponses, stimulating adhesion molecule and chemoattractant production. Hydrogen peroxide,
which breaks down to produce hydroxyl radicals, can also activate NF-κB, a transcription fac-
torinvolvedinstimulatinginflammatoryresponses.Excessproductionofthesereactivespecies
istoxic,exertingcytostaticeffects,causingmembranedamage,andactivatingpathwaysofcell
death (apoptosis and/or necrosis).
Virtually all diseases thus far examined involve free radicals. In most cases, free radicals
aresecondarytothediseaseprocess,butinsomeinstancesfreeradicalsarecausal.Thus,there
is a delicate balance between oxidants and antioxidants in health and disease. Their proper
balance is essential for ensuring healthy aging.
Thetermoxidativestressindicatesthattheantioxidantstatusofcellsandtissuesisaltered
by exposure to oxidants. The redox status is thus dependent on the degree to which a cell’s
componentsareintheoxidizedstate.Ingeneral,thereducingenvironmentinsidecellshelpsto
preventoxidativedamage.Inthisreducingenvironment,disulfidebonds(S—S)donotsponta-
neouslyformbecausesulfhydrylgroupskeptinthereducedstate(SH)preventproteinmisfold-
ing or aggregation. This reducing environment is maintained by oxidative metabolism and by
theactionofantioxidantenzymesandsubstances,suchasglutathione,thioredoxin,vitaminsE
andC,andenzymessuchassuperoxidedismutase(SOD),catalase,andtheselenium-dependent
glutathione and thioredoxin hydroperoxidases, which serve to remove reactive oxygen species.
Changesintheredoxstatusanddepletionofantioxidantsoccurduringoxidativestress.The
thiolredoxstatusisausefulindexofoxidativestressmainlybecausemetabolismandNADPH-
dependent enzymes maintain cell glutathione (GSH) almost completely in its reduced state.
Oxidized glutathione (glutathione disulfide, GSSG) accumulates under conditions of oxidant
exposure, and this changes the ratio of oxidized to reduced glutathione; an increased ratio
indicates oxidative stress. Many tissues contain large amounts of glutathione, 2–4 mM in
erythrocytesorneuraltissuesandupto8mMinhepatictissues.Reactiveoxygenandnitrogen
species can directly react with glutathione to lower the levels of this substance, the cell’s
primary preventative antioxidant.
Currenthypothesesfavortheideathatloweringoxidativestresscanhaveaclinicalbenefit.
Free radicals can be overproduced or the natural antioxidant system defenses weakened, first
resulting in oxidative stress, and then leading to oxidative injury and disease. Examples of
this process include heart disease and cancer. Oxidation of human low-density lipoproteins is
consideredthefirststepintheprogressionandeventualdevelopmentofatherosclerosis,leading
to cardiovascular disease. Oxidative DNA damage initiates carcinogenesis.
Compelling support for the involvement of free radicals in disease development comes
from epidemiological studies showing that an enhanced antioxidant status is associated with
reducedriskofseveraldiseases.VitaminEandpreventionofcardiovasculardiseaseisanotable
example. Elevated antioxidant status is also associated with decreased incidence of cataracts
and cancer, and some recent reports have suggested an inverse correlation between antioxidant
status and occurrence of rheumatoid arthritis and diabetes mellitus. Indeed, the number of
indications in which antioxidants may be useful in the prevention and/or the treatment of
disease is increasing.
Oxidativestress,ratherthanbeingtheprimarycauseofdisease,ismoreoftenasecondary
complicationinmanydisorders.Oxidativestressdiseasesincludeinflammatoryboweldiseases,
retinal ischemia, cardiovascular disease and restenosis, AIDS, ARDS, and neurodegenerative
diseases such as stroke, Parkinson’s disease, and Alzheimer’s disease. Such indications may
Series Introduction v
proveamenabletoantioxidanttreatmentbecausethereisaclearinvolvementofoxidativeinjury
in these disorders.
In this new series of books, the importance of oxidative stress in diseases associated
with organ systems of the body will be highlighted by exploring the scientific evidence and
the medical applications of this knowledge. The series will also highlight the major natural
antioxidant enzymes and antioxidant substances such as vitamins E, A, and C, flavonoids,
polyphenols, carotenoids, lipoic acid, and other nutrients present in food and beverages.
Oxidative stress is an underlying factor in health and disease. More and more evidence
indicates that a proper balance between oxidants and antioxidants is involved in maintaining
healthandlongevityandthatalteringthisbalanceinfavorofoxidantsmayresultinpathological
responsescausingfunctionaldisordersanddisease.Thisseriesisintendedforresearchersinthe
basicbiomedicalsciencesandclinicians.Thepotentialforhealthyaginganddiseaseprevention
necessitates gaining further knowledge about how oxidants and antioxidants affect biological
systems.
Rapid progress in the application of antioxidant substances and other micronutrients war-
rantedarevisionandupdateofHandbookofAntioxidants,highlightingnewfundamentalstud-
ies on food-derived antioxidants and biomarkers, vitamins E and C, coenzyme Q, carotenoids,
flavonoids and other polyphenols, antioxidants in beverages and herbal products, the thiol
antioxidants glutathione and lipoic acid, melatonin, selenium, and nitric oxide. Handbook of
Antioxidants: Second Edition, Revised and Expanded, is an authoritative volume regarding the
chemical, biological, and clinical aspects of antioxidant molecules. The individual chapters
provide an in-depth account of the current knowledge of vitamins or other naturally occurring
antioxidant compounds and discuss critically the new aspects of antioxidant therapy. We are
delightedtohavebeeninvolvedwiththisprojectandaregratefultotheauthorsinthisvolume
for their outstanding contributions.
Lester Packer
Enrique Cadenas

Preface
The Handbook of Antioxidants: Second Edition, Revised and Expanded, is an authoritative
treatiseonthechemical,biological,andclinicalaspectsofantioxidantmolecules.Eachchapter
providesanin-depthaccountofthecurrentknowledgeofvitaminsorothernaturallyoccurring
antioxidant compounds and discusses critically the new aspects of antioxidant therapy.
About100millionAmericansarenowusingfoodsupplementsthathaveantioxidantactiv-
ity, and there is an urgent need for providing the scientific community and the general public
with the most current information available.
The biochemistry of reactive oxygen species is an important field with vast implications.
Whereas oxygen is an essential component for living organisms, the generation of reactive
oxygen species seems to be commonplace in aerobically metabolizing cells. Cells convene
substantial resources to protect themselves against the potentially damaging effects of reac-
tive species. The first line of defense against these free radicals is composed by enzymes,
such as superoxide dismutase, glutathione peroxidase, and catalase, and several vitamins and
micronutrients, which actively quench these free radical species or are required as cofactors
for antioxidant enzymes. The cellular antioxidant status and its role in fighting progression
of certain disease processes associated with oxidative stress have gained potential therapeutic
significance in view of the beneficial effects of free-radical-scavenging drugs or antioxidants.
Likewise,epidemiologicalstudiesemphasizetherelevanceofantioxidantvitaminsandnutrients
in health issues and/or prevention of chronic and degenerative diseases of aging.
Rapid progress in the application of antioxidant substances and other micronutrients war-
ranted a revision of Handbook of Antioxidants. This updated edition highlights new funda-
mental studies on food-derived antioxidants and biomarkers, vitamins E and C, coenzyme Q,
carotenoids, flavonoids and other polyphenols, antioxidants in beverages and herbal products,
the thiol antioxidants glutathione and lipoic acid, and melatonin, selenium, and nitric oxide.
Wearedelightedtohavebeeninvolvedwiththisprojectandthankthecontributorstothis
volume for their outstanding efforts.
Enrique Cadenas
Lester Packer
vii

Contents
Series Introduction (Lester Packer and Enrique Cadenas) iii
Preface vii
Contributors xiii
I. General Topics
1. Food-Derived Antioxidants: How to Evaluate Their Importance in Food
and In Vivo 1
Barry Halliwell
2. Measurement of Total Antioxidant Capacity in Nutritional and Clinical Studies 47
Guohua Cao and Ronald L. Prior
3. Quantification of Isoprostanes as Indicators of Oxidant Stress In Vivo 57
Jason D. Morrow, William E. Zackert, Daniel S. Van der Ende, Erin E. Reich,
Erin S. Terry, Brian Cox, Stephanie C. Sanchez, Thomas J. Montine, and
L. Jackson Roberts
II. Vitamin E
4. Efficacy of Vitamin E in Human Health and Disease 75
Sharon V. Landvik, Anthony T. Diplock, and Lester Packer
5. Vitamin E Bioavailability, Biokinetics, and Metabolism 99
Maret G. Traber
6. Biological Activity of Tocotrienols 109
Stefan U. Weber and Gerald Rimbach
ix