Nutraceuticals in Health and Disease Prevention (Oxidative Stress and Disease) PDF
Preview Nutraceuticals in Health and Disease Prevention (Oxidative Stress and Disease)
ISBN: 0-8247-0492-4 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http://www.dekker.com Thepublisheroffersdiscountsonthisbookwhenorderedinbulkquantities.For moreinformation,writetoSpecialSales/ProfessionalMarketingattheheadquar- ters address above. Copyright (cid:211) 2001 by Marcel Dekker, Inc. All Rights Reserved. Neitherthisbooknoranypartmaybereproducedortransmittedin anyformor by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without per- mission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA Series Introduction Oxygen is a dangerous friend. Overwhelming evidence indicates that oxidative stresscanleadtocellandtissueinjury.However,thesamefreeradicalsthatare generated during oxidative stress are produced during normal metabolism and thus are involved in both human health and disease. Free radicals are molecules with an odd number of electrons. The odd, or unpaired,electronishighlyreactiveasitseekstopairwithanotherfree electron. Free radicals are generated during oxidative metabolism and energy pro- duction in the body. 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 Normalmetabolismisdependentuponoxygen,afreeradical.Throughevo- lution,oxygenwaschosen astheterminalelectronacceptorforrespiration.The two unpaired electrons of oxygen spin in the same direction; thus, oxygen is a biradical, but is not a very dangerous free radical. Other oxygen-derived free radicalspecies,such assuperoxideorhydroxylradicals,formedduringmetabo- lism or by ionizing radiation are stronger oxidants and are therefore more dan- gerous. In addition to research on the biological effects of these reactive oxygen species, research on reactive nitrogen species has been gathering momentum. NO,ornitrogenmonoxide(nitricoxide),isafreeradicalgeneratedbyNO syn- thase (NOS). This enzyme modulates physiological responses such as vasodila- iii iv SeriesIntroduction tion or signaling in the brain. However, during inflammation, synthesis of NOS (iNOS) is induced. This iNOS can result in the overproduction of NO, causing 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 canresult, therebyincreasingthe likelihoodoftissueinjury. Bothreactiveoxygenandnitrogenspeciesareinvolvedinnormalcellregu- lation in which oxidants and redox status are important in signal transduction. Oxidativestressisincreasinglyseenasamajorupstreamcomponentinthesignal- ing cascade involved in inflammatory responses, stimulating adhesion molecule andchemoattractantproduction.Hydrogenperoxide,whichbreaksdowntopro- ducehydroxyl radicals,canalsoactivate NF-k B,atranscription factorinvolved in stimulating inflammatoryresponses. Excess production ofthese reactive spe- ciesistoxic,exertingcytostaticeffects,causingmembranedamage,andactivat- ing pathways of cell death (apoptosis and/or necrosis). Virtuallyalldiseasesthusfarexaminedinvolvefreeradicals.Inmostcases, free radicals are secondary to the disease process, but in some instances free radicalsarecausal.Thus,thereisadelicatebalancebetweenoxidantsandantioxi- dantsinhealthanddisease.Theirproperbalanceisessentialforensuringhealthy aging. The term oxidative stress indicates that the antioxidant status of cells and tissues is altered by exposure to oxidants. The redox status is thus dependent uponthedegreetowhichacell’scomponentsareintheoxidizedstate.Ingeneral, thereducingenvironmentinsidecellshelpstopreventoxidativedamage.Inthis reducing environment, disulfide bonds (S—S) do not spontaneously form be- causesulfhydrylgroupskeptinthereducedstate(SH)preventproteinmisfolding or aggregation. This reducing environment is maintained by oxidative metabo- lism and by the action of antioxidant enzymes and substances, such as glutathi- one, thioredoxin, vitamins E and C, and enzymes such as superoxide dismutase (SOD),catalase,andtheselenium-dependentglutathioneandthioredoxinhydro- peroxidases, which serve to remove reactive oxygen species. Changes in the redox status and depletion of antioxidants occur during oxidativestress.Thethiolredoxstatusisausefulindexofoxidativestressmainly because metabolism and NADPH-dependent enzymes maintain cell glutathione (GSH)almostcompletelyin itsreducedstate.Oxidizedglutathione(glutathione disulfide, GSSG) accumulates under conditions of oxidant exposure, and this changestheratioofoxidizedtoreducedglutathione;anincreasedratioindicates oxidativestress.Manytissuescontainlargeamounts ofglutathione,2–4mMin erythrocytesorneuraltissuesandupto8mMinhepatictissues.Reactiveoxygen and nitrogen species can directly react with glutathione to lower the levels of this substance, the cell’s primary preventative antioxidant. Current hypotheses favor the idea that lowering oxidative stress can have a clinical benefit. Free radicals can be overproduced or the natural antioxidant SeriesIntroduction v systemdefensesweakened,firstresultinginoxidativestress,andthenleadingto oxidativeinjuryanddisease.Examplesofthisprocessincludeheartdiseaseand cancer. Oxidation of human low-density lipoproteins is considered the first step intheprogressionandeventualdevelopmentofatherosclerosis,leadingtocardio- vascular disease. Oxidative DNA damage initiates carcinogenesis. Compellingsupportfortheinvolvementoffreeradicalsindiseasedevelop- mentcomesfromepidemiologicalstudiesshowingthatanenhancedantioxidant statusisassociatedwithreducedriskofseveraldiseases.VitaminEandpreven- tion of cardiovascular disease is a notable 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 andoccurrenceofrheumatoidarthritisanddiabetesmellitus.Indeed,thenumber of indications in which antioxidants may be useful in the prevention and/or the treatment of disease is increasing. Oxidative stress, rather than being the primary cause of disease, is more often a secondary complication in many disorders. Oxidative stress diseases in- clude inflammatory bowel disease, retinal ischemia, cardiovascular disease and restenosis,AIDS,ARDS,andneurodegenerativediseasessuchasstroke,Parkin- son’s disease, and Alzheimer’s disease. Such indications may prove amenable toantioxidanttreatmentbecausethereisaclearinvolvementofoxidativeinjury 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 sub- stances such as vitamins E 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 moreevidenceisaccumulatingthataproperbalancebetweenoxidantsandanti- oxidants is involved in maintaining health and longevity and that altering this balance in favor of oxidants may result in pathological responses causing func- tional disorders and disease. This series is intended for researchers in the basic biomedical sciences and clinicians. The potential for healthy aging and disease preventionnecessitatesgainingfurtherknowledgeabouthowoxidantsand anti- oxidants affect biological systems. As we move into the twenty-first century, new functions of nutrients en- compassedbytheirinvolvementincell-signalingcascadeshavebeenrecognized. These functions are beyond their antioxidant activity and effects on the cellular balancebetweenoxidantsandantioxidants.Theso-calledfunctionalfoods,nutra- ceuticals,andoptimalfoodsareunderdevelopmentandcommercialization.The introduction of proteomics and genomics permits us to ascribe biological func- tionstofoodcomponents.Asmightbeexpected,thishasstrengthenedthedevel- vi SeriesIntroduction opmentof‘‘designerfoods’’aimedatimprovinghealth,promotinghealthyaging, and preventing disease. This volumein the Oxidative Stressand Disease seriesincludes contribu- tionsanddiscussionsofsomefoodcomponentsandnutraceuticals,theirputative mechanisms of action, and their implications for health and disease. Lester Packer Enrique Cadenas Preface The past decade has seen an enormous shift in our concept of nutrition. We have moved far beyond the goal of providing nutrition adequate to avoid the developmentofdeficiencystatestothatofpreventingortreatingchronicdiseases thathavereplacedinfectiousdiseasesasourmajorkillers:cancer,heartdisease, and diabetes. We have already made astonishing strides toward achieving this goal. For example, it is now accepted that supplementation with vitamin E, at levels impossible to achieve in the diet, can reduce the risk of heart disease. Thepaceofresearchisconstantlyaccelerating,andithasbecomedifficult fortheaveragehealthprofessionaltokeepupwiththeastoundingachievements that have become almost routine. For this reason, ‘‘The New Approach to a HealthyLife: WorkshoponNutraceuticals,’’aconferenceheldonDec.3,1998 in Ludwigshafen, Germany, was organized. The purpose of the meeting was to bringtogetherthelatestdevelopmentsinresearchonnutritionalsubstancesused fordiseasepreventionandtherapy—substancesthat havebeendesignated‘‘nu- traceuticals.’’ This volume includes the highlights reported at that meeting and willbeofinteresttohealthpractitionersandresearchers,aswellasanyoneinter- estedinlearningmoreaboutthestudiesthatarequietlyrevolutionizingthefield of nutrition. During the first 85 years of the 20th century, the average human lifespan increased. This was mainly due to a 60% reduction in mortality. Major factors contributingtothisremarkableoccurrencewereimprovedhygieneandnutrition, and medical advances, particularly the control of infectious diseases. We can forseefurtherimprovementsinthequalityoflifethatwillleadtotheemergence of centenarians as a significant actuarial class, including more powerful means ofmaintainingthebody’sdelicatebalancebetweenenvironmentalstressors(oxi- dants)andourantioxidantdefensesystem.Nutraceuticals,theso-calleddesigner orfunctionalfoods,canbeexpectedtoprovidethemostsignificantimprovements and developments. vii viii Preface Adefinitionfornutraceuticalsremainssomewhatelusive.Simplyput,they are‘‘foodsspecificallyformulatedtodeliverhealthbenefits.’’Amoreextensive definition states that a nutraceutical is a food, or any part of a food, that offers a health benefit above and beyond providing simple nutrition or basic fortifica- tion.Underthisdefinition,thehealthbenefitmayincludethepreventionortreat- mentofdiseaseortheenhancementofthebody’sfunctioning(FoodTechnology 1998; 52(6):44). Perhaps the broadest definition of a nutraceutical has been formulated by StevenL.DeFelice,M.D.,asfollows:‘‘Anutraceuticalisanysubstancethatis a food or part of a food and provides medical or health benefits, including the prevention and/or treatment of disease. Such products may range from isolated nutrients,dietarysupplements,anddietstogeneticallyengineereddesignerfoods, herbalproducts,andprocessedfoodssuchascereals,soups,andbeverages.Itis important to note that this definition applies to all categories of foods and parts of food.’’ Manyorganizations,includingmajorcorporations,researchinstitutes,and university laboratories, are seeking to identify methods of optimizing nutrition thatwillproducehealthyagingandaqualitylifespan.Thisincludescombinations oftheapproximately40micronutrientsthathavebeenidentified,researched,and reported in the nutritional literature for years. But molecular nutrition is a rela- tivelynewfield.Thehealthconsequencesofdeficiencyofoneoracombination ofseveralmicronutrientsarelargelyunknown.Ontheothersideofthecoinare thebeneficialeffectsthatmaybeproducedbyintakeofmicronutrientsatlevels above the recommended daily allowance (RDA) or daily recommended intake (DRI).Addedtothechallengearethevaryingneedsofhumanbeingsofdifferent genders,ages,and environments.The fieldisstillin itsinfancy,andidentifying thecombinationsofnutrientsthatmayoptimizehealthfortheyoung,theelderly, men, women, various ethnic groups, and people in different areas of the world (orindeeddifferentregionswithinaparticularcountry)requiresidentificationof theneedsnotonlyoftheentirepopulationintheseregions,butalsoofsubpopula- tions. At present, such detailed data are limited. Nevertheless, many exciting developments have occurred that show the promise of this young but rapidly emerging field of research and development. Inaddition,geneticengineeringofexistingfoodsourcesisgainingmomen- tum. One example are tomatoes engineered to enhance their lycopene content. Fortification with biofactors in amounts and forms far exceeding the levels in a diet composed of unmodified foodstuffs may someday be as routine for fruits and vegetables as it is now for fortified cereals. We anticipate that new fields of research will be developed. Molecular nutritionand molecular biologywill cometogetherto identify foodfactors,and thelessonstaughtbytraditionalmedicinewillbeupdatedusingthetoolsofmod- ern medicine. Preface ix Toillustratetheunprecedentedexpansionofthisfieldofresearch,thisbook includes a few examples of areas in which nutraceuticals have been developed and shown to be effective. The first several chapters are devoted to overviews andperspectivesonthisemergingfield.Chapter1introducesthebasicconcepts relatingnutraceuticalstobothmaintenanceofhealthandpreventionortreatment of pathology. Chapter 2 offers a perspective on nutraceuticals as they relate to ourcurrenttheoriesofaging,especiallyconcerningthehealthbenefitsofsupple- mentalvitaminEandtheconceptoftheantioxidantnetwork.Anexcitingdevel- opment in research on depression, arthritis, and inflammatory diseases is the emergenceofS-adenosyl-l-methionine,anaturallyoccurringsubstancewithfew side effects. This is discussed from a general perspective in Chapter 3 and with respect to joint diseases in Chapter 4. One aspect of nutraceutical research is identifying the optimal form in which to provide a nutrient, as exemplified in Chapter5onmethyltetrahydrofolate.Wehavenowreachedthesecondgeneration ofcarotenoidresearch,withthefocusshiftingawayfrombeta-caroteneto more balancedmixtures;Chapter6discusseslycopeneandlutein,twocarotenoidsthat areemergingashighlyeffectivedisease-preventingagents.Anexampleofshift- ingnutritionalbalancestooptimizeintakeofthemorebeneficialnutrientsisthe realization that polyunsaturated fatty acids (PUFAs) and, in particular, certain classes of PUFAs may be a key component of a healthy diet. This is discussed from a clinical perspective in Chapter 7. Lipoic (thioctic) acid has long been knownasanessentialcofactorinmetabolismandisnowrecognizedasapowerful antioxidant with great preventive and therapeutic potential. Chapter 8 provides a summary of the multiple uses of this powerful substance. Chapter 9 focuses on its metabolic aspects, in terms of both its function and its beneficial effects on cellular metabolism. Finally, Chapter 10 discusses creatine, which has been shown to be a safe and effective anabolic nutraceutical currently used by thou- sandsofathletesandweekendwarriorstopromotestrength.Otherchapters(11– 13) discuss the health effects of polyphenols, carnitine, and conjugated linoleic acid. Important research directions and regulatory issues are the topics covered in Chapters 14 and 15. The first heyday in nutritional evolution came when most of the essential factorsforpreventionofacutenutritionaldisorders(suchasscurvyandberiberi) were identified. The challenge that now awaits us is to go beyond the baseline requirements for survival to optimize nutrition, the major factor influencing our quality of life. Nutraceuticals will be developed from established knowledge of caloric requirements for essential substances in the diet, and from elucidation of the many components in the food chain whose benefits are not yet fully known. Plants have survived through evolutionary adaptations that protect them from environmentalstressors.Thesemolecularadaptationsoftenarealsoprotectivein humanbeings,buttheanalysisoftheliterallythousandsofcompoundscontained
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