Natural antioxidants in human health and disease

593 Pages·1994·61.24 MB·English

by  Balz Frei

NATURAL ANTIOXIDANTS
IN HUMAN HEALTH
AND DISEASE
Edited by
BALZ FREI
Harvard School ofPublic Health
Boston, Massachusetts
ACADEMIC PRESS
San Diego New York Boston London
Sydney Tokyo Toronto
Contributors
Numbers inparentheses indicate the pageson whichthe authors' contributions begin.
Bruce N. Ames (63), Department of Molecular and Cell Biology, Division of
BiochemistryandMolecularBiology,UniversityofCaliforniaat Berkeley,Berke
ley,California 94720
Adrianne Bendich (447), Human Nutrition Research, Hoffman-La RocheIncorpo
rated, Nutley, NewJersey07110
Gladys Block (129), School of Public Health, University ofCalifornia at Berkeley,
Berkeley, California 94720
Karlis Briviba (107), Institut fur Physiologische Chemie I, Heinrich-Heine
Universitat Dusseldorf, D-4000-Dusseldorf I, Germany
Leo T. Chylack, Jr. (515), Division of Ophthalmology, Brigham and Women's
Hospital, andDepartmentofOphthalmology, Centerfor Ophthalmic Research,
Harvard Medical School, Boston, Massachusetts 02115
Kuldeep R. Dhariwal (469),Section ofCell Biology andBiochemistry, Laboratory
ofCell Biology andGenetics, National Institute of Diabetes andDigestive and
Kidney Diseases, National Institutes of Health, Bethesda,Maryland 20892
Elizabeth T. H. Fontham (I 57),StanleyS. ScottCancerCenterand,Department
ofPathology,LouisianaStateUniversityMedicalCenter, NewOrleans, Louisiana
70112
Balz Frei (303, 353), Departments of Medicine and Biochemistry, and Whitaker
Cardiovascular Institute, Boston University SchoolofMedicine, Boston, Massa
chusetts 02118
xv
xvi / Contributors
Miriam Garland (263), Department of Epidemiology, Harvard School of Public
Health, Boston, Massachusetts 021 I5
J. Michael Gaziano (387), Divisions of Preventive Medicine and Cardiology,
Brigham and Women's Hospital, and Harvard Medical School, Boston, Massa-
chusetts 02215
Charles H. Hennekens (387), Division of Preventive Medicine, Department of
Ambulatory Care and Prevention, Harvard Medical School, Boston, Massa-
chusetts 02215
David J. Hunter (263), Department of Epidemiology, Harvard School of Public
Health, and The Channing Laboratory, Department of Medicine, Harvard Medi-
cal School and Brigham and Women's Hospital, Boston, Massachusetts 02115
Paul F.Jacques (515), United States Departmentof Agriculture, Human Nutrition
Research Center on Aging, Tufts University, Boston, Massachusetts 021 II
David R.Janero (411), Research Department, Ciba Pharmaceuticals, Summit, New
Jersey 0790I
John F. Keaney,Jr. (303), EvansMemorial Departmentof Medicine, and Whitaker
Cardiovascular Institute, Boston University School of Medicine, Boston, Massa-
chusetts 021 18
James P. Kehrer (25), Division of Pharmacology and Toxicology, College of Phar-
macy,The University of Texas at Austin, Austin, Texas 78712
Paul Knekt (199), Research and DevelopmentCentre, The Social Insurance Institu-
tion, Helsinki, 00380 Finland
Norman I. Krinsky (239), Departmentof Biochemistry, Tufts UniversitySchool of
Medicine, Boston, Massachusetts 021 II
Sharon Landvik (567), Vitamin EResearch and Information Service, Edina, Minne-
sota 55436
Mark Levine (469), Section of Cell Biology and Biochemistry, Laboratory of Cell
Biology and Genetics, National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health, Bethesda, Maryland 20892
Sean M. Lynch (353), WhitakerCardiovascular Institute, Boston UniversitySchool
of Medicine, Boston, Massachusetts 021 18
JoAnn E. Manson (387), Division of Preventive Medicine, and The Channing Labo-
ratory Department of Medicine, Brigham and Women's Hospital, and Harvard
Medical School, Boston, Massachusetts 02215
David P. R.Muller (535), Division of Biochemistryand Genetics, Institute of Child
Health, London WCIN IEH, United Kingdom
Lester Packer (567), Department of Molecular and Cell Biology, University of
California at Berkeley, Berkeley, California 94720
Jae B. Park (469), Section of Cell Biology and Biochemistry, Laboratory of Cell
Biology and Genetics, National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health, Bethesda, Maryland 20892
Ernst Peterhans (489), Institute of Veterinary Virology, University of Berne,
CH-30I2 Berne, Switzerland
Contributors / xvii
William A. Pryor (I), Biodynamics Institute, Louisiana State University Baton
Rouge, Louisiana 70803
Abraham Z. Reznick (567), Department of Morphological Sciences, The Bruce
Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa,
Israel
ColinJ. Schwartz (287), Departmentof Pathology, The UniversityofTexas Health
Science Center, San Antonio, Texas 78284
Richard Schwarz (129), Lawrence Berkeley Laboratory, Life Sciences Division,
University of California at Berkeley Berkeley, California 94720
Mark K. Shigenaga (63), Department of Molecular and Cell Biology,Division of
Biochemistryand MolecularBiology,UniversityofCaliforniaat Berkeley, Berke-
ley,California 94720
Helmut Sies (I07), Institut fur Physiologische Chemie I, Heinrich-Heine-
Universitat Dusseldorf, D-4000-Dusseldorf I, Germany
Charles V. Smith (25), Department of Pediatrics, Baylor College of Medicine,
Houston, Texas 77030
Meir J. Stampfer (263), Departments of Epidemiology and Nutrition, Harvard
Schoolof Public Health,and TheChanningLaboratory, DepartmentofMedicine,
Harvard Medical School and Brigham and Women's Hospital, Boston, Massa-
chusetts 021 I5
Allen Taylor (515), United States Department of Agriculture, Human Nutrition
Research Center on Aging, Tufts University, Boston, Massachusetts 021 II
Anthony J. Valente (287), Department of Pathology, The University of Texas
Health Science Center, San Antonio, Texas 78284
Yaohui Wang (469), Section of Cell Biology and Biochemistry, Laboratory of Cell
Biology and Genetics, National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health, Bethesda, Maryland 20892
Richard W. Welch (469), Section of Cell Biology and Biochemistry, Laboratory of
Cell Biology and Genetics, National Institute of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
Walter C. Willett (263), Departments of Epidemiology and Nutrition, Harvard
Schoolof Public Health,and TheChanning Laboratory, Departmentof Medicine,
Harvard Medical School and Brigham and Women's Hospital, Boston, Massa-
chusetts 021 I5
8
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Copyright© 1994byACADEMICPRESS, INC.
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Library of Congress Cataloging-in-Publication Data
Natural antioxidantsinhuman health anddisease / edited byBalz
Frei.
p. em.
Includes bibliographicalreferencesandindex.
ISBN:0-12-266975-4
1. Active oxygen. 2. Antioxidants. 3. Membranelipids-
-Peroxidation. 4. Free radicals (Chemistry)--Pathophysiology.
I. Frei,Balz.
[DNLM: 1. Antioxidants--therapeuticuse. 2. FreeRadicals.
3. Oxidants--adverseeffects. QV800N285 1994]
RB170.N39 1994
616.07'I--dc20
DNLM/DLC
forLibrary ofCongress 94-7646
CIP
Transferredtodigitalprinting 2006
94 95 96 97 98 99 EB 9 8 7 6 5 4 3 2 1
Foreword
Metabolism, like otheraspects of life, involves trade-offs. Oxidantby-products
of normal metabolism cause extensive damage to DNA, proteins, and lipids. This
damage(the same asthatproducedbyradiation)appears tobeamajor contributorto
aging and to degenerative diseases of aging such as cancer, cardiovasculardisease,
cataracts, immune system decline, and brain dysfunction. Antioxidant defenses
against this damage include ascorbate (vitamin C), tocopherol (vitamin E), and
carotenoids, the main dietary sources of which are associated with fruit and vege-
table intake. Low dietary intake of fruits and vegetables doubles the risk of most
types ofcanceras comparedto high intake and may also markedlyincreasethe risk
ofcardiovascular disease and cataracts. Given that only 9% ofAmericans eat the
recommended five servings of fruits and vegetables per day, the opportunity for
improving health by improving diet is great.
Evolutionary biologists have argued that aging is inevitable because of several
trade-offs. One trade-offisthat aconsiderableproportionofananimal'sresources is
devoted to reproduction at a cost to maintenance, which means that the mainte-
nance of somatictissues isless than that requiredfor indefinite survival. Ofthe vast
array of maintenance processes that are necessary to sustain normal function in
somatic cells, those that defend the cell against metabolism-derived oxidants are
likely to play an important role. Metabolism has costs: oxidant by-products of
normalenergymetabolismextensivelydamageDNA, proteins, andothermolecules
in the cell, and this damage accumulates with age. Another trade-off is that nature
selects for many genes that have immediate survival value, but that may have long-
term deleterious consequences. The oxidative burst from phagocytic cells, for ex-
xix
xx / Foreword
ample, protects against death from bacterial and viral infections, but contributes to
DNA damage, mutation, and cancer.
Oxidation and Damage to DNA, Proteins, and Lipids
Oxidative damage to DNA, proteins, and other macromolecules accumulates
with age and has been postulatedtobe amajor, but nottheonly,type ofendogenous
damage leading to aging. Superoxide (0;), hydrogen peroxide (H202), and hy-
droxyl radical (HO·), which are the mutagens produced by radiation, are also by-
products of normal metabolism. Lipid peroxidation gives rise to mutagenic lipid
epoxides, lipid hydroperoxides, lipid alkoxyl and peroxyl radicals, and enals (a,r3-
unsaturated aldehydes). Singletoxygen (102), ahigh energy and mutagenic form of
oxygen, can beproducedbytransferofenergyfrom light, therespiratoryburst from
neutrophils, or lipid peroxidation.
Animals have numerous antioxidant defenses, but because these defenses are
not perfect, some DNA is oxidized. Oxidatively damaged DNA is repaired by
enzymes that excise the lesions, which are then excreted in the urine. Methods
have been developedtoassay several ofthese exciseddamaged bases inthe urine of
rodents and humans, almost all of which appear as the free base from repair by
glycosylases. Weestimatethat the numberofoxidativehits toDNA per cell per day
is about 100,000 in the rat and about 10,000 in the human. DNA repair enzymes
efficiently remove most, but not all, of the lesions formed. Oxidative lesions in
DNA accumulate with age, sothat bythe time arat isold (2years), ithas about two
million ONA lesions per cell, which is about twice that in a young rat. Mutations
also accumulate with age. For example, the somatic mutation frequency in human
lymphocytes, of which the contribution of oxidative DNA lesions is unknown, is
about nine times greater in elderly people than in neonates. The importance of
oxidativeDNA lesions inmutationisunderscoredbythe existenceofspecific repair
glycosylases that excise these lesions from DNA. In the case of 8-hydroxy-2'-
deoxyguanosine, a lesion formed from oxidative damage to guanine residues in
DNA, loss ofa specific glycosylase activity leads to an appreciable increase in the
spontaneous mutationrate, indicating the intrinsic mutagenic potentialofthis DNA
lesion. Other oxidative DNA lesions are likely to be important as well.
Mitochondrial DNA (mtDNA) from rat liver has more than ten times the level
of oxidative DNA damage ofnuclear DNA from the same tissue. The cell defends
itselfagainst this high rate of damage by a constant turnoverof mitochondria, thus
presumably removing those damaged mitochondria that produce increased quan-
tities ofoxidants. Despitethis turnover, oxidativelesions appeartoaccumulate with
age in mtDNA at a higher rate than in nuclear DNA. Oxidative damage could also
account for the mutations in mtDNA that accumulate with age.
Endogenous oxidants also damage proteins and lipids. Earl Stadtman and his
colleagues have shown that the proteolytic enzymes that hydrolyze oxidized pro-
teins are not sufficient topreventan age-associated increaseof oxidizedproteins. In
two human diseases associated with premature aging, Werner's syndrome and pro-
Foreword / xxi
geria, oxidized proteins increase at a much higher rate than is normal. Fluorescent
pigments, which are thought to be due in part to cross-links between protein and
lipid peroxidation products, also increase with age.
Sourcesand Effectsof Oxidants
Four endogenous sources appear to account for most of the oxidants produced
bycells: (1)Asaconsequenceofnormal aerobic respiration, mitochondriaconsume
molecular oxygen, reducing it by sequential steps to produce H 0. Inevitable by-
2
products of this process, as stated above, are Or, H202, and HO-. About 1012
oxygen molecules are processed by each rat cell daily, and the leakage of partially
reduced oxygen molecules is about 2%, yielding about 2 x 1010 superoxide and
hydrogenperoxidemolecules percell perday. (2)Phagocytic cells d°estroy bacteria-
orvirus-infectedcells with anoxidative burst of nitric oxide (-NO), 2-,H202, and
hypochlorite(-OCI). Chronic infection byviruses, bacteria, orparasites results ina
chronic phagocytic activity and consequent chronic inflammation, which isamajor
risk factor for cancer. Chronic infections are particularly prevalent in Third World
countries (see below). (3) Peroxisomes, which are organelles responsible for de-
grading fatty acids and other molecules, produce H 0 as a by-product, which is
2 2
then degraded by catalase. Evidence suggests that, under certain conditions, some
ofthe peroxideescapesdegradation, resulting initsrelease intoother compartments
ofthe cell and inincreasedoxidativeDNA damage. (4)CytochromeP-450enzymes
in animals constitute one of the primary defense systems against natural toxic
chemicals from plants, the major source of dietary toxins. The induction of these
enzymes prevents acute toxic effects from foreign chemicals, but also results in
oxidant by-products that damage DNA.
Three exogenous sources may significantly increase the large endogenous oxi-
dant load. (1) Iron (and copper) salts promote the generation of oxidizing radicals
from peroxides(Fenton chemistry). Men who absorb significantly morethan normal
amounts of dietary iron (hemochromatosis disease) are at an increased risk for both
cancer and heart disease. It has therefore been argued that too much dietary copper
or iron, particularly heme iron (which is high in meat), is a risk factor for heart
disease and cancer in normal men. (2) The oxides of nitrogen (NOx) in cigarette
smoke (about 1000 ppm) cause oxidation of macromolecules and deplete antioxi-
dant levels. This is likely to contribute signficantly to the pathology of smoking.
Smoking is a risk factor for heart disease as well as a wide variety of cancers in
addition to lung cancer. (3) Normal diets contain plant food with large amounts of
natural phenoliccompounds, such aschlorogenicandcaffeic acid, that can generate
oxidants by redox cycling.
Chronic Infection, Inflammation, and Cancer
As mentioned above, leukocytes and other phagocytic cells combat bacteria-,
parasite-, and virus-infected cells by destroying them with -NO, Or, H202, and
xxii / Foreword
-OCI, apowerful oxidantmixture. These oxidants protecthumans from immediate
death from infection, but cause oxidative damage to DNA and mutation, thereby
contributing to the carcinogenic process. Antioxidants appearto inhibit some of the
pathology ofchronic inflammation (see below).
Chronicinfectionscontributetoabout one-thirdofthe world'scancer. Hepatitis
BandC viruses infect about 500 million people, mainly inAsia and Africa, and are
a major cause of hepatocellular carcinoma. Another major chronic infection is
schistosomiasis, which is caused by a parasitic worm that is widespread in China
and Egypt. The Chinese worm lays its eggs in the colon, producing inflammation
that often leads to colon cancer. The Egyptian worm lays its eggs in the bladder,
promoting bladder cancer. Opisthorchis viverrini, a liver fluke, infects millions of
peopleinThailandand Malaysia. The flukes lodge inbile ducts and increasetherisk
of cholangiocarcinoma. Chlonorchis sinensis infections in millions of Chinese in-
crease their risk for biliary tract cancer. Helicobacterpylori bacteria, which infect
the stomachsofover one-thirdofthe world population, appeartobethe major cause
ofstomach cancer, ulcers, and gastritis. In wealthy countries the disease is usually
asymptomatic, which indicates that the effects ofinflammation are at least partially
suppressed, possibly by adequate levels of dietary antioxidants.
Chronic inflammation resulting from noninfectious sources also contributes to
various pathological conditions leading to cancer. For example, asbestos exposure
causing chronic inflammation may in good part be the reason it isa significant risk
factor for cancer of the lung.
Antioxidants Protect against Disease
Many defense mechanisms have evolved within the organismto limit the levels
ofreactive oxidants and the damage they inflict. Among the defenses are enzymes
such assuperoxidedismutase, catalase, andglutathioneperoxidase. The glutathione
S-transferases inactivate reactive electrophilic mutagens, including the aldehyde
products of lipid peroxidation. There are also many structural defenses such as
sequestering H 0 enzymes in peroxisomes and chelating any free iron
2 2-generating
orcoppersalts intransferrinand ferritin orceruloplasmintoavoidFentonchemistry.
Oxidized DNA is repaired by nonspecific excision repair enzymes and, more
importantly, by a series of glycosylases that are specific for particular oxidized
bases. In the absence of cell division these oxidative lesions are dealt with quite
effectively and the mutation rate is kept to a minimum. Oxidized proteins are
degraded by proteases. Lipid hydroperoxides are destroyed by glutathione perox-
idase. Almostallofthese defenses appeartobeinducible, asare mostothertypes of
defenses; i.e., the amounts increase in response to use. There is much literature
showing that cells respond to low levels of radiation, an oxidative mutagen, by
inducing antioxidant defenses that help to protect them against mutation by high
levels of radiation. There is a trade-off, however, since the induction of these
defenses makes the cell more sensitive to alkylating mutagens.
Foreword / xxiii
Consumption of dietary antioxidants that are presentin fruits and vegetables is
associated with alowered risk of degenerative diseases inaddition tothe protective
effects of endogenous enzymatic antioxidant defenses. Gladys Block and her col-
leagues have recently reviewed 172 studies in the epidemiological literature that
relate, with great consistency, the inadequate consumption of fruits and vegetables
to increasedcancerincidence. The quarterof the population with the lowest dietary
intake of fruits and vegetables, comparedto the quarterwith the highest intake, has
double the cancer rate for most types of cancer (lung, larynx, oral cavity, esopha-
gus, stomach, colon and rectum, bladder, pancreas, cervix, andovary). Dataonthe
types of cancer known to be associated with hormone levels are not as consistent
and show less protection by fruits and vegetables: for breast cancer the protective
effect was about 30%. There is also literature on the protective effect of fruit and
vegetable consumption on cardiovascular disease and stroke. Only 9% of Ameri-
cans eat five servings of fruits and vegetables per day, the intake recommended by
the National Cancer Institute and the National Research Council. European coun-
tries with low fruit and vegetable intake (e.g., Scotland) are generally in poorer
health and have higher rates of cardiovascular disease and cancer than countries
with high intake (e.g., Greece).
Dietary Antioxidants
The effectofdietary intake oftheantioxidantsascorbate, tocopherol, andcarot-
enoids is difficult to disentangle from the effects of other important vitamins and
ingredients in fruits and vegetables by epidemiological studies. Nevertheless, sev-
eral arguments suggest that the antioxidant content of fruits and vegetables is a
majorcontributorto their protectiveeffect. (1) Biochemical data, discussed above,
show that oxidative damage is massive and is likely to be the major endogenous
damage to DNA, proteins, and lipids. (2) Studies from our laboratory show that
oxidativedamage tosperm DNA isincreasedwhen dietary ascorbate isinsufficient.
(3) Epidemiological studies and intervention trials on prevention of cancer and
cardiovascular disease in people taking antioxidant supplements are suggestive,
though more studies need to be done. Clinical trials using antioxidants will be the
critical test for many of the ideas discussed here. (4) Studies on oxidative mecha-
nisms and epidemiology on antioxidant protection for individual degenerative dis-
eases discussed in this book are also suggestive.
Small-molecule dietary antioxidants such as ascorbate, tocopherol, and carot-
enoids have generated particular interest as anticarcinogens and asdefenses against
degenerative diseases. Most carotenoids have antioxidant activity, particularly
against singlet oxygen and many, including ~-carotene, can be metabolized to
vitamin A (retinal). We have called attention to a number of previously neglected
physiological antioxidants including urate, bilirubin, carnosine, and ubiquinol.
Ubiquinone, for example, isthe critical small molecule fortransportingelectrons in
mitochondria for the generation of energy. Its reduced form, ubiquinol, is aneffec-