Namiki 1990

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Critical Reviews in Food Science and Nutrition

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Antioxidants/antimutagens in food
a
Mitsuo Namiki
a
Department of Brewing and Fermentation, Tokyo University of Agriculture, Setagayo‐ku,
Sakuragaoka, 1–1–1, Tokyo, 156, Japan
Version of record first published: 29 Sep 2009
To cite this article: Mitsuo Namiki (1990): Antioxidants/antimutagens in food, Critical Reviews in Food Science and Nutrition,
29:4, 273-300
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Food Science and Nutrition
Antioxidants/Antimutagens in Food Here recent advances in the search for natural antioxidants,
their chemistry, and their biological function at the cellular
Mitsuo Namiki and body level are reviewed, including studies on antimuta-
genicity of antioxidative food constituents and natural
substances.
Because they have been throughly reviewed elsewhere for
I. INTRODUCTION their biological functions and other features, tocopherol, as-
corbic acid, and their related compounds are for the most part
Food and oxygen, the two fundamentals of human life, are excluded from this discussion.
in actuality involved in intricately conflicting interactions. This
review focuses on the study of these interactions.
The deterioration of food with time, deterioration that results II. ACTIVE OXYGEN SPECIES AND
from its largely biological nature, is inevitable. During the FORMATION OF LIPID PEROXIDES
production, processing, distribution, and storage preceding ac-
tual consumption, food undergoes various modes of deterio- A. Triplet Oxygen
ration that involve biological changes by microbes as well as Oxygen, which constitutes 20.9% of air, is paramagnetic,
being a biradical in triplet (3S~) state with two electrons in
Downloaded by [University of Arizona] at 11:45 21 July 2012
chemical changes. The latter is represented by enzymatic and

nonenzymatic oxidation of lipids and phenolic substances, which separate parallel antibonding orbitals. Due to this peculiarity,
cause undesirable changes in flavor, appearance, physical char- oxygen molecules have weaker interatomic bonding than ni-
acter, nutritional value, and toxicity. Deoxygenation, airtight trogen molecules and can form complexes with oxygen carrier
packaging, and other techniques have solved some of these as electron acceptor (Figure 1). Triplet oxygen can react with
problems, but the role of antioxidants as either food constit- elements and ions to form oxides, but usually not with organic
uents or as additives cannot be overlooked. compounds that are in singlet states. However, it reacts easily
Despite the fact that we depend on biological oxidation as with free radical molecules produced by the action of other
a source of energy for survival and activity, the action of active radicals, radiation, ultraviolet light, heat, or by complex
oxygen is really two-sided. The powerful reactivity of active formation with oxygen and transition metal ions to produce
oxygen species can cause functional damage to man, triggering active peroxide radicals and trigger autoxidation of unsaturated
mutagenesis, carcinogenesis, circulatory disturbances, and ag- fatty acids and others.
ing,1"3 even though we are in part depending on it for metab-
olism of foreign matter, prostaglandin biosynthesis,6 and B. Active Oxygen
antibacterial cell activities. Besides SOD7 (superoxide dis- Highly reactive oxygen molecules and oxygen radicals are
mutase), catalase, glutathione peroxidase, and other enzyme generated from the triplet state oxygen by excitation or reduc-
systems that act in our body to destroy the active oxygen tion. Oxygen thus activated is called active oxygen and is
species, food-derived matter such as tocopherol (vitamin E8), important in the degradation of food as well as in other bio-
ascorbic acid (vitamin C), carotenoids, etc. are considered to logical oxygen effects.17-18
be active in eradicating active oxygen species and suppressing The energetically more stable form of the excited oxygen
their effects.1-2 molecule is the singlet state oxygen,19 having two higher and
BHA and BHT, the most widely used artificial antioxidants, lower energy states,1 A g and 1 £+. The former is labile and
have unsurpassed efficacy in various food systems besides their has a shorter life, while the latter can interact with unsaturated
high stability, low cost, and other practical advantages. How- bonds. Singlet oxygen is obtained mainly by photoexcitation
ever, their use in food has been falling off due to suspected in the presence of initiator dyes such as methylene blue and
action as a promoter of carcinogenesis9"13 as well as due to a chlorophyll. Singlet oxygen usually cannot dehydrogenate or-
general rejection of synthetic food additives,14"16 especially in ganic compounds, but can react with unsaturated bonds of, for
Japan. Tocopherol and ascorbic acid derivatives that are being example, unsaturated fatty acids. In such cases, reaction occurs
used as BHA and BHT substituents are much less effective as mainly by ene-reactions involving allylic hydrogen, which pro-
food antioxidants, and the development of more effective an- duce hydroperoxides. Peroxides are also produced through ad-
tioxidants of natural origins is desirable, even though they may dition reactions, for example, dioxethane formation by 1,2-
not be comparable in efficiency to synthetic agents. Such new
antioxidants would also be welcome in combatting carcino-
genesis as well as the aging process.
The relationship between food and oxygen is thus very com-
plex. From this viewpoint, antioxidants in food are in them- M. Namiki, B.S., Dr., Prof., Department of Brewing and Fermen-
selves indispensable constituents of food, comparable in tation, Tokyo University of Agriculture, Setagayo-ku, Sakuragaoka,
1-1-1, Tokyo, Japan 156.
importance with other nutritive constituents for our survival.
1990 273
Critical Reviews In
Triplet Singlet Singlet

Name oxygen oxygen Superoxide
oxygen
Symbol •o, 01
"A,
Potential 0 22.5 37.5 -9.9
energy(Kcal/mol)
(H) intermolecular 1.2074 1.2155 1.2268 1.28-1.35
distance
Electron
configuration n M 2
and Orbital P o
11) filJ
a*2s
o2s (Y)
ff"ls Cit)
als
FIGURE 1. Physical properties and electron configuration of oxygen molecules.18
addition and endoperoxide formation by 1,4-addition to dienes tential to produce highly reactive HO- radical through the Fen-
(Figure 2).18-19 ton reaction (peroxide and Fe(II) and the Haber-Weiss reaction
Since the singlet oxygen is produced mainly by photoexci- (superoxide and H2 O2; Of + H2 O2 -*• HO- + HO~ + O2).
tation and since peroxide formation by singlet oxygen does not The Haber-Weiss reaction is considered too slow in itself to
trigger a radical chain reaction, it is not usually attributed very be significant in biological systems, but can produce the HO*
much importance in biological systems.19 In food systems con- radical when Fe ion is present by the production of Fe(II) by
taining heme iron and chlorophylls, however, it can induce O2 followed by the Fenton reaction between H2 O2 and Fe(II).
active oxygen radicals leading to autoxidation of unsaturated The HO- radical produced by radiolysis of water is extremely
fatty acid under light. reactive and constitutes the main factor in so-called oxygen
The oxygen molecule behaves in biological reactions as an toxicity. It reacts with all biological materials oxidatively by
electron acceptor and forms water by a 4-electron reduction. hydrogen withdrawal, double bond addition, electron transfer,
Most oxidation enzymes work by 4-electron reduction, but and radical formation, and initiates autoxidation, polymeri-
some of them reduce step wise 1-electron reductions. One-elec- zation, and fragmentation.
tron reduction of oxygen, which is thermodynamically less The reactivity of active oxygen species is summarized in
favorable, produces superoxide HO2 or Of The superoxide is Table 1. As is well known, peroxidation followed by decom-
degraded into oxygen and hydrogen peroxide by dispropor- position or polymerization of unsaturated fatty acids proceeds
tionation reaction. The hydrogen peroxide is fairly stable, but through hydrogen withdrawal from the active methylene group
has weak bonding energy and bond distance longer than that adjacent to the unsaturated bond, reaction of the produced
of the oxygen molecule, and undergoes 1-electron reduction radical with triplet oxygen to form peroxy radical ROO-, and
for form HO* and water. The former also produces water by subsequently hydrogen peroxide ROOH by chain reactions.
further reaction, as shown in Figure 3. Although ROOH is not highly reactive, it gives HO- and RO-
Superoxide Oj, which is given much attention in biological radicals in the presence of, for example, Fe ion, or decomposes
studies, is not a highly reactive radical in itself. Fe(III) is to fragments of the fatty acid molecule to give reactive carbonyl
reduced to Fe(II), while ascorbic acid is oxidized by Oj but compounds and others. A summarized scheme is shown in
oxidation of fatty materials is not initiated by O j Hydrogen Figure 4.
peroxide is also low in activity to initiate lipid peroxidation. At least two paths are known for the formation of lipid
Their activity as active oxygen species comes from their po- peroxides in vivo.20 One occurs through autoxidation of cate-
274 Volume 29, Issue 4

Sen + hv *• Sen*
3
Sen* + 0 , ( JS,-) •—*• Sen + ' 0 2
'Sen + 0 , (>S,-) > Sen + 'O, (XJ, o r
'Sen-
Sen-
Ene-reaction
H
v x= + "0,
\r
0
\
CH=CH
+
CH2''
OOH OH
N
CH-CH CH=CH
CH2 CH;
/OOH
.CH=CH + .CH^CH y CH-CH
FIGURE 2. Singlet oxygen. Formation by photosensitization and ene reaction.
cholamine, thiols, quinones, and others, and redox reactions the substrate to peroxide, which is decomposed by cytochrome
of oxyhemoglobin and myoglobin, and the other from active P-450 to radicals that initiate lipid peroxidation (see Figure 5).
oxygen by the action of xanthine oxidase, NADPH oxidase,
and other enzymes. Lipids are peroxidized in liver microsomes,
but different opinions exist for its mode of initiation. Fong et III. ACTIVE OXYGEN RADICAL SPECIES
al.21 attribute it to the action of the reduced form of NADH- AND INDUCED EFFECTS—MUTAGENESIS,
cytochrome P-450 reductase, which converts molecular oxygen CARCINOGENESIS, AGING AND OTHERS
to CT2 and then to H O . Aust and co-workers22 prefer a scheme
involving reduction of ADP-Fe(III) by NADPH-cytochrome Induction of mutagenesis, the best known of the biological
reductase to form oxygen and perferryl ion and oxidation of effects of radiation, occurs mainly through damage of DNA
1990 275
Critical Reviews In
e- +2H4
H2O
Cytochrome oxidase complex
Catalases
Peroxidase
—OH* •np
superoxide
dismutases
FIGURE 3 . The univalent pathway for reduction of molecular oxygen and enzymatic mech-
anisms to bypass and prevent the accumulation of reactive intermediates.203
Table 1 covery systems; for example, by repair enzymes, which, on

Reactivity of Active Oxygen Species 18 the other hand, some agents are known to act as promoters in
these processes. In studies on the mechanisms of various types
Reaction rate kM~ l s - 1 of mutagens and carcinogens, some are said to be related to
' N
c— a the active oxygen species.23 For example, quinone type anti-
fy-t tumor agents such as adriamycine are assumed to produce
Name Structure I
RC1 C)
superoxide, and lipid peroxides are suspected of being re-
sponsible for the activation of benzo(a)pyrene and other car-
Hydroxy radical HO- 105 10' 0
106
cinogens, as well as for the production of some types of
Alkoxy radical LO- 106 0
Hydroperoxy radical HO2 102 10 0 promoter.
Peroxy radical LOj 102 10 0 Not much is known about the mechanism of aging and what
Fe-oxygen complex Fe-O 2 ? 7 7 determines lifespan; leading theories attribute these to programs
Superoxide Ol 0 0 103 written into DNA and/or to the accumulation of cellular and
Hydrogen peroxide H2O2 0 slow 0 functional damage." Formation of lipid peroxide and subse-
Hydroperoxide LOOH 0 slow 0 quent damage to cell membrane and DNA are considered very
Singlet oxygen 'Oj 0 105 0
important in the latter theory. The action of the HO* radical is
Ozone o Slow 105 0
considered directly responsible for the damage, but not much
••" abstraction of allylic hydrogen is known as to whether superoxide and other species are ex-
—»- H X + tensively involved. Model experiments for verifying the in-
volvement of superoxide have shown that scission of T-7 phage
)
l addition to double bond DNA by K2O is inhibited by superoxide scavenger,24 and that
I I chromosome aberration induced by superoxides is inhibited by
SOD (superoxide dismutase), catalase, and by scavengers for
x-c-c. the HO* radical.25 So far, however, the HO* radical is consid-
reaction with C-Cl bond ered to be the main direct agent in oxygen toxicity.
O; + RCl In vivo, both enzymatic and nonezymatic systems work pro-
+ cr tectively against peroxidation. SOD, which contains copper,
by the HO* radical and other species produced by radiolysis of zinc, iron, and/or manganese and is distributed widely from
water, and also by direct radiation effect on DNA. The reac- bacteria to mammals, decomposes superoxide into H2 O2 and
tions of HO* radicals are mainly addition to double bond of O2 by disproportionation reaction.7 Catalase, too, decomposes
pyrimidine bases and abstraction of hydrogen from the sugar H2 O2 to oxygen and water, and glutathione peroxidase also
moiety resulting in chain scission of DNA. These effects can decomposes H2 O2 to water.
cause cell mutagenesis and carcinogenesis. The processes, The action of vitamins as nonenzymatic protective agents is
however, are not simple, because cells usually have some re- discussed in the following section.

m13
H
9
H
yrryH H H H
\—LOO- 1 500 50,000 500 1
-LOOH
OOH OOH
(III)
S yo,
O,J|/O, J2
t •00 /
LH
L- j-H
o2
M (IV)
OH A
V (ID
A=-(CH2)7 COOH;B = -(CH2)4 CH3;I=9-trans, cis-LOOH; II =13-

trans, trans-LOOH; 111 = 13-trans. cis-LOOH; IV =9-trans. trans-LOOH.
FIGURE 4. Autoxidation of linoeic acid (LH) and relative reactivity of its C-H bond with peroxy radical.18
IV. FUNCTION OF ANTIOXIDANTS IN FOOD propionic acid are capable of decomposing peroxides. Amino
AND IN BIOLOGICAL SYSTEM acids such as tryptophan, histidine, and methionine also act
antioxidatively, probably as electron donors responsbile for
Factors promoting the oxidation of food and the means for their nitrogen or sulfur atoms and partly their metal chelating
its suppression are summarized in Table 2. Removal of oxygen activity. P-Carotene, tocopherol, and others eliminate singlet
is the primary means of suppression. Inactivation of oxidation oxygen. Citric acid, ascorbic acid and other food components
enzymes, protection against light, and removal of metal ions chelate heavy metal ions and suppress peroxidation catalyzed
are also important, but these measures are not always applicable by the metal ions. Ascorbic acid can be linked with tocopherol
in actual systems. The use of added antioxidants therefore in biochemical redox reaction systems and enhances antioxi-
becomes no less important and sometimes their synergistic dative action.26-27 Natural antioxidants very often have multiple
action by other means can be effective. modes of action that have not been clarified fully.
Table 3 summarizes the function of antioxidants in relation Many studies have been conducted on biological systems
to the formation and action of active oxygen species. As radical regarding the preventive action of vitamin E, C, and A on
scavengers, phenolic antioxidants widely distributed in plants peroxidation. Briefly surveyed, vitamin E is the most important
work either as hydrogen donors or as electron donors that form in this sense since it is oxidized by fatty acid radicals generated
charge-transfer complexes. Some phenols, amines, and dithio- by peroxidation and regenerated by vitamin C and glutathi-
1990 277
Critical Reviews In
PERFERRYL ION-DEPENDENT
ADP-Fe INITIATION
NADPH- Cyt./»- 450

Reductase
LOOH
XO LIPID HYDROPEROXIDE-DEPENDENT
Xanthine Urate
INITIATION
EDTA- Fe J T
o .^—^ o
2 SOD
+0
NADP
ÊDTA-fe'*
NADPH
NADPH- Cyt. i"- Cytochrome p-450

EDTA-feJ
Reductase
Cytochrome ^ - 4 5 0 Destruction
LOOH
L00-. L0-. L-.O*
IH- 't DPF
END PRODUCTS
FIGURE 5. Schematic of the proposed mechanisms for lipid peroxidation.22
one.28 Vitamin E reacts with the R O O radical and also with idant action of ascorbic acid has also been observed in an oil-
singlet oxygen, although p-carotene is more rapid and efficient casein or oil-cellulose mixture at relatively high moisture
in the latter.29 Besides the aforementioned redox conjugation content.35
with vitamin E, vitamin C deactivates ' O / 0 and O j 3 1 in vitro, Besides the action of the above vitamins, suppression of
and scavenges the HO- radical in neutral media and is generally lipid peroxidation by vitamin B 2 36 and ubiquinone37 through
considered to be a suppressant of peroxidation.32 However, the their correlating enzymes is known, and antioxidative action
possibility of its inverse action as a prooxidant in the presence of uric acid38-39 and bilirubin40 has also been reported recently.
of iron and copper ions has been pointed out.33-34 The proox- It must be borne in mind that at this time very little is known

Table 2 Table 4
Factors Affecting Peroxidation Measurements of Lipid Peroxidation
Promotion Suppression Peroxide value (POV)

Iodometry: ROOH + 2KI - » ROH + I2 + K2O
Unsaturated fatty acid Reduction to saturated fatty acid Thiocyanate method: ROOH + Fe2* -» ROH + HO- + Fe 3+
Oxygen, active oxygens Gas exchange, oxygen removal Measurements of decomposition products
Vacuum packaging Carbonyl value (colorimetry with 2,4-DNP derivative)
Heavy metal ions and chelated compounds Removal of metal ions TBA value (colorimetry with thiobarbituric acid)
Metal chelation Gas chromatography
Light and dyes Removal of dyes; shielding GC-MS method
Radiation Radical scavenger Measurements of oxygen consumption
Peroxide-free radical Antioxidant Dissolved oxygen meter
Heating Refrigeration Weighting method
Moisture content Intermediate moisture Warburg manometer
Lipoxigenase Enzyme inactivation Physicochemical methods
UV absorption (conjugated double bond)
Table 3 IR spectrometry
ESR spectrometry
Functions of Antioxidants Fluorescence
Chemiluminescence
Radical scavenger
Hydrogen donor
Electron donor
peroxidation in food and biological systems,44 even though the
Peroxide decomposer coloration is influenced considerably by various reaction con-
Singlet oxygen quencher ditions,45 and the TBA value observed in biological and food
Enzyme inhibitor materials does not necessarily indicate the amounts of lipid
Synergist hydroperoxide.46
Metal chelating agent: reducing agent
Gas chromatographic analysis of volatile products of per-
oxidation, for example, ethane produced by oxidative frag-'
about the real functions and mechanisms of action of vitamins mentation of the alkoxy radical of unsaturated fatty acids, is
and other antioxidants in living systems; studies are generally often used on expiration of a biological body47 because of its
scattered and sometimes speculative. More time is required for advantage of allowing continuation of experiments without sac-
the accumulation of data and the formation of a broad general rifice; the results, however, appear to be subject to fluctuation.
picture. The GC-MS method became useful for the highly sensitive
determination of lipid peroxidation products by the recent de-
V. CHEMICAL AND PHYSICOCHEMICAL velopment of analytical methods such as fast atom bombard-
EVALUATION OF ANTIOXIDANT ACTIVITY ment (FAB) with its use of the computer.48 Measurement of
decrease of dissolved oxygen in solution by oxygen meter or
The process of formation of lipid peroxide can be studied of increase in weight, which is accompanied by oxidation, is
by various chemical and physicochemical measurements of simple and convenient, but the object systems are rather limited.
peroxide reactivity, radical formation, determination of oxi- Measurement of absorption at 234 nm of conjugated double
dation products, oxygen and fatty acids, etc. Analytical meth- bond is a simple method for estimation of autoxidation, but is
ods widely used for this purpose are summarized in Table 4. more often useless for living systems absorbing in this region.
The efficacy of antioxidants is usually evaluated by deter- Amperometric measurements based on the reaction LOOH +
mination of lipid peroxides, but it is necessary to use different 2e"+2H + -»LOH + H2O (L = fatty acid) has been conveni-
methods to study the mechanics of antioxidative activity and ently utilized in combination with HPLC.49 ESR method is
for the evaluation of practical usefulness as a food antioxidant. specifically sensitive to free radical,50 but its direct application
Determination of lipid hydroperoxide, peroxide value (POV), to lipid oxidation systems is difficult for the extremely short
by iodometry41 or Fe thiocyanate colorimetry42 is widely uti- lives of free radicals in these systems, and the spin-trapping
lized in in vitro studies. Simplified methods using POV paper43 method is applicable to food and biological systems.51 The
or test solution have been developed recently and are conve- degree of oxidation in dried foods is estimable by ESR method,
nient for determination of fat food peroxidation. which responds to free radical species, remaining stable in
One of the analytical methods for oxidation products in- proteins and other matrices.52
volves determination of the formed carbonyl compounds, mainly Schiff bases, produced by reactions of carbonyl compounds
malonaldehyde (MAD). Colorimetry of MAD using thiobar- produced from lipid peroxides with amino compounds, often
bituric acid (TBA) is a popular method for estimation of lipid give luminescence. A luminescent substance called lipofuscin
1990 279
Critical Reviews In
found in aged human tissue is believed to be of this kind and EDTA-chelated Fe(II) ion, which can be formed directly from
is measurable by excitation at 350 to 360 nm and luminescence EDTA-Fe(m) by NADPH-cytochrome P-450 reductase, or in-
at 420 to 450 n m . " directly by superoxide (ADP-Fe(m)/EDTA-Fe(ffl)/NADPH
Chemiluminescence (CL) method measures very weak lu- system). These systems were used as model biological systems
minescence-like emission given off by molecules excited by in our studies for evaluation of antioxidative activity, using
reaction with active oxygen or other elements and are now the TBA method for peroxide determination. A peroxidation-
utilizable for ultramicro analysis of active oxygen or peroxide, initiating system with adriamycin was also used. In this case,
with the aid of luminol, luciferin and other luminescent re- adriamycin, an anthracyclin antibiotic with strong antitumor
agents, advanced detectors, and HPLC. The luminescence by action, sometimes exerts cardiac toxicity, which is assumed to
the reaction of luminol with peroxy radical and singlet oxygen, be attributable to the formation of superoxide radical by its
which is generated by oxidation of hydroperoxides with added quinone-like structure followed by lipid peroxidation.56"58
cytochrome C, is used for determination of hydroperoxides.
Marked increase of luminescent intensity in liver of mouse fed VII. SCREENING OF NATURAL
with methyl linoleate and methyl hydroperoxide has been
ANTIOXIDANTS
observed.54
In this field of study, careful consideration concerning the Materials available for screening for natural antioxidants are
applicability of the method on the object systems and data summarized in Table 5.
interpretation is essential, because the complexities of food or
biological systems can often upset the validity of the existing Table 5
analytical systems. Natural Antioxidants
VI. EVALUATION OF ANTIOXIDANTS IN Plant

Oilseeds
MODEL BIOLOGICAL SYSTEMS Grains
Beans
The activity of most food antioxidants has been screened Vegetables, Emits
and evaluated using POV and other methods described in the Leaf waxes
Bark and root
preceding section, but that of their activities in biological sys-
Spices
tems has to depend on animal tests. If some convenient in vifro Medicinal plants
methods of evaluation linking chemical and biological methods Seaweeds
can be established, the results would be very productive. We Microbial products
have examined the efficacy of antioxidants against induced Animal products
peroxidation, using two model systems containing biological Fermented products
Protein hydrolysates
membranes with high contents of phospholipids involving highly Maillard reaction products
unsaturated fatty acids.55 Others
A. Erythrocyte Membrane System Life forms living in the Earth's atmosphere must be equipped
In this sytem, the suppressive effect of antioxidants on per- with systems to deal with the action of oxygen on living matter.
oxidation induced by tert-butyl peroxide on ghost membrane Plants that are exposed to visual and ultraviolet light and ra-
of rat erythrocyte is measured by the TBA method. A me- diation are especially susceptible to damage by active oxygen
chanistic study of antioxidative action has been done using this and oxygen toxicity, and plant constituents; for example, to-
system with the aid of spin-trapping ESR measurements. copherol, carotene, and phenolic matter act as antioxidants to
counter oxygen radicals and excited molecules. Oxidation of
B. Rat Liver Microsome System phenols, especially polyphenols by polyphenoloxidase, also led
This system contains highly unsaturated fatty acids and is to the formation of polymers that act to protect tissue, as well
known to be peroxidized in biological systems in the presence as to the formation of structural lignin. Plant seeds and germs
of NADPH and cytochrome P-450 reductase. Peroxidation oc- rich in lipids (especially in oil-producing plants) and adjacent
curs through two routes, as shown in Figure 5. 23 tissue must be adequately protected against oxygen, and prob-
In one, hydroperoxide of unsaturated fatty acid is produced ably contain effective antioxidants. Some kinds of plant seeds
by initiation with perferryl ion formed by the direct reduction retain their germination power for surprisingly long periods,
of ADP-chelated iron with NADPH-cytochrome P-450 reduc- and it is reasonable to assume that all plant seeds have efficient
tase and molecular oxygen (ADP-Fe(II)/NADPH system) or systems involving antioxidants to protect their germination
by the reduction of oxygen to superoxide. In the other case, mechanism in germs and in surrounding tissues.
lipid hydroperoxide-dependent initiation can be promoted by Looking back, mankind has accumulated hundreds of years

of experience with respect to preservation of food. Humans than other types of vegetable oil. Figure 6 compares autoxi-
have also gained much knowledge about foods considered to dation of common vegetable oils at 60°C. Common salad oil
contribute to health and longevity. While much of the infor- (a mixture of soybean and rapeseed oils), corn oil, and saf-
mation may not stand up to close scientific scrutiny, at least flower oil are rapidly oxidized after 10 to 20 d incubation, but
part may prove justifiable and enlightening, revised from the both sesame oils remain unaltered even after 50 d.64 Subsequent
standpoint of the role of oxygen and antioxidants in human chemical study showed that the content of sesamol, which is
life. Many antioxidants that have been found in nature can be believed to be the main antioxidant in the sesame oils, is very
reinterpreted from the above view, which has motivated the low in roasted sesame oil and showed only trace amounts in
screening work being continued in our laboratory. unroasted refined sesame oil.65 Further studies on the antiox-
The actions of tocopherol, ascorbic acid, carotenes, and idative constituents in sesame and sesame oils revealed the
other antioxidants have been reviewed thoroughly and are not compounds shown in Figure 7 to be the effective antioxidants.66
discussed here. The following section introduces recent studies Among these compounds, four lignanphenols were newly found
concerning other kinds of antioxidants. to be characteristic of sesame seed and oil. Sesamolinol67 and
sesaminol,68 which are new substances, were stereochemically
studied using X-ray analysis and also compared for the an-
VIII. NEWER NATURAL AND FOOD- tioxidative activities of their isomers.69 It was found that se-
RELATED ANTIOXIDANTS saminol, which is found in high content in purified unroasted

sesame oil and has been shown to be its main antioxidative
A. Sesame constituent, is present in sesame seed only in minor quan-
Sesame is assumed to have originated in the savannah of tities.65 This difference was found to be due to the high-yield
central Africa and has a history of 6000 years as the oldest conversion of sesamolin to sesaminol by intermolecular group
cultivated oil-seed plant. It spread from ancient Egypt to India, transfer catalyzed by acid clay used for decolorization (Figure
China, and then the rest of the world.59 From ancient times, 8). 70 It is interesting to be note that sesaminol is possibly an
sesame has been considered to be a valuable oil-seed not only effective constituent of Justicia simplex, a traditional Hima^
because of its high oil content, but also because of its medicinal layan medicinal plant.71
effects. An ancient Chinese natural history book promotes se-
same as a food that increases energy and prevents aging. The 10
oil content of sesame is higher than 50%, and the oil fatty
acids are mainly oleic and linoleic acid.60-61 It exceeds 20%
protein content, containing larger amounts of arginine, leucine,
and methionine than FAO values. Compared with soybean,
3
lysine content is lower, but methionine and cystine contents
are higher, so their parallel use makes for high-quality food.
Sesame is also rich in minerals, iron, and calcium. However, h
a
such nutritional value alone does not sufficiently explain the v
traditional high position sesame holds as a health food.
The high resistance of sesame oil to oxidation compared
with other vegetable oils has long been known, but has not
been fully explained on a scientific basis. It has been attributed
to the presence of a phenolic compound, sesamol, which is 0 10 20 30 40 50
produced from sesamolin, a lignan characteristic to sesame.61-62 Incubation time (60°C, day)
The author's laboratory has carried out a series of studies on
FIGURE 6. Stability of oils stored at 60°C. - • - Safflower
its resistance to oxidation.59-63
oil; - D - mixture of soybean and rapeseed oils; - ^ - com oil; -
Two kinds of sesame oil are currently produced. The dif- A-unroasted sesame oil; -O- roasted sesame oil.65
ference is found in the use of roasted or unroasted raw sesame
seeds for pressing and in the purification process employed. The reason for the especially high stability of oil from roasted
Roasted sesame seed oil is only filtered to remove contami- sesame has not been clarified fully, but the presence of 7-
nants, while oil from unroasted seed is decolorized by acid tocopherol and minor amounts of sesamol as well as the pres-
clay and deodorized by vacuum steam-distillation.63 Roasted ence of products of the Maillard reaction by roasting may be
oil has a characteristic flavor and a brown color and is widely responsible.72 In this connection, it has been found that sesa-
used in China, Korea, and Japan for seasoning and cooking, molin is hydrolyzed during the use of the oil for frying to
while the unroasted raw-pressed oil is used in Euro-American produce sesamol and contributes to the stability of fried food.73
countries and in Japan mainly for salad dressing and frying.63 Pinoresinol, another antioxidant constituent, has been found in
Both kinds have markedly higher stability against autoxidation other plants and is known to inhibit cAMP phosphodiesterase.74
1990 281
Critical Reviews In
(A)
OCH3
Sesamin || Sesamolin
O
0.2-0.5%(seed) 0.2~0.3%(seed)
(B)
CH3
y-Tocopherol Sesamol
OCH3
0—I OCH3
PI Sesaminol Pinoresinol
H3CO OCH3
CH=CHCOOH
Syringic acid Ferulic acid Sesamol dimer
FIGURE 7. Sesame lignans (A) and antioxidants (B) (* only in S. angolense).*
B. Rice germination potential of rice seed may possibly be related to

Germ of rice seeds is rich in oil and is known to contain antioxidative activity. With this in mind, a series of studies
orizanol and tocopherol as antioxidants.75-76 In Japan, rice were carried out on representative Indica and Japonica species
stocked at ordinary temperature decreases in quality and price differing in germination potential, on peroxide formation dur-
in contrast to India, where 1-year stocked rice is said to be ing high temperature-storage and with 7-irradiation, and on
preferred to new rice. Difference in cooking and taste may be the antioxidative activity of their components. It was shown
the reason for this, but the difference in rice species, Japonica that storage at 60°C resulted in a complete loss of germination
and Indica, could also be the reason. According to a routine after 45 d in the case of Kusabue (Japonica species), while
test for new and stocked rice by germination ratio, the decrease Katakutara (Indica species) retained a germination potential
in germination ratio by storage at room temperature is generally well above 95%, and corresponding increase in POV (TBA
smaller for Indica than that for Japonica, and especially so for test) of extracted lipids, a marked increase in Kusabue and loV
Katakutara and Century Patna species, as shown in Figure increase in Katakutara.79
9.77>78 The cause of the loss of germination ability has not yet Interestingly, those species showing strong antioxidative ac-
been elucidated, but a major focus is damage to the intracellular tivity in the storage test at room temperature and at 60°C showed
membrane structure. This damage may be causally related to low POV and low residual free radical formation after irradia-
peroxidation of lipid moieties of seeds, so the difference in the tion with 7-rays, and also a smaller decrease in germination

r-o
FIGURE 8. Scheme for the mechanism of formation of sesaminol from sesamolin.70 (1) Sesamolin, (2) sesaminol, (3) oxonium
ion, (4) sesamol (5) m-Cresol, (6) new lignan derivative, (7) samin ethanolysate, (8) samin. (a) Camphorsulfonic acid in toluene,
heat in model system, and decolorization with acid clay in sesame oil purification; (b) buffer (pH 1.0), EtOH, heat in model system,
and in frying of foods.
ratio compared with others80 (Figure 10). In this irradiation- zanol.82 Fractionation of the extracts by HPLC gave several
induced peroxidation, the effects were apparently more sup- active fractions richer in phenolic substances. Isolation and
pressed in the case of irradiation of rice with hull than in the identification of active components from these fractions indi-
case of irradiation of rice without hull. This irradiation also cated that isovitexin, a C-glycosyl flavonoid, is one of the
induced changes in fatty acid composition, that is, a decrease active antioxidants in rice hull (Figure 12); it was as active as
in the linoleic acid content in phospholipids with the increase a-tocopherol in antioxidative activity and effectively scav-
in irradiation doses and a corresponding increase in the linoleic enged the HO- radical.83 The presence of such antioxidants in
acid content in the free fatty acid. A marked decrease in the hulls, which was not known hitherto, induce many challenging
tocopherol content was observed in rice seed irradiated without problems regarding, for example, their role in the preservation
hull, especially in the case of Japonica rice species.81 of plant seeds.
Antioxidative assay using different solvent extracts of hull,
bran-germ, and grain fractions of two Indica and five Japonica C. Spices
rice varieties indicated that the seed varieties high in germi- The use of spices has been highly valued from prehistorical
nation potential posses strong antioxidative activity, especially times not soley because of their flavor, but also because of
in the hull (Figure 11). Quantification of the known antioxi- their food-preserving power, knowledge of which was gained
dants in rice seeds, that is, a-tocopherol and oryzanol, indi- through experience. A number of studies have been done on
cated no positive correlation between the antioxidative activity their antioxidative activity, as well as on their antiseptic activity.
of rice hull and the content of these natural antioxidants.78 First, Dubois84 showed antioxidative action of sage, mace,
Subsequent chemical search for the antioxidants in rice showed black pepper, and others on frozen meat. Then Chipault85-86
that the methanol extracts of rice hull from Katakutara have showed effective antioxidative activity of solvent extracts of
stronger antioxidative activity than a-tocopherol and ory- Perilla plants (rosemary, sage, thyme, etc.) on lard. Other
1990 283
Critical Reviews In
100 ether extracts of rosemary and sage were as effective as

BHA. 8789
Recently, four effective antioxidants were isolated by Nak-
atani et al.90"92 in hexane extract of dried rosemary leaves (1
to 4 in Figure 13 [numbers in parentheses in this section refer
to those in the cited figure]) and among these rosmanol showed
activity stronger than BHA in lard as well as in a water-oil
emulsion system.90-91 These four are odorless and tasteless di-
I terpenelactones having an o-diphenolic group on the C ring,
o which is responsible for antioxidative activity. The same com-
pounds have been isolated from sage.93 Several of two allyl-
s phenols and nine lignans isolated from papua mace (Myristica
argentea warb.) showed strong antioxidative activity.94
Rosamaridiphenol (5) and rosmariquinone (6) isolated from
rosemary by Ho et al.95-96 are reported to be as effective as
BHA and BHT. A phenolic derivative of caffeic acid, a di-
phenol glycoside (7), rosemaric acid (8), and its new derivative
(9), and caffeic acid have been isolated as antioxidative com-
ponents from methanol extract of hexane-extracted leaves of
Storage period (months) oregano (Origanum vulgare L.), aPerilla plant.97-98 This meth-
anol extract is applicable as a water-soluble antioxidant with
FIGURE 9. Effect of storage on germination ability of Indica (In) and activity much higher than that of tocopherol.
Japonica (Jap) rice seeds.73 (-•-), Katakutara (In); (-O-), Century patna
Five biphenol derivatives related to thymol have been iso-
(In); ( - • - ) , Koshihikari (Jpn.); (-D-), Kusabue (Jpn.); (-£,-), Sachiwatari
(Jpn.); (-A-), Himenomochi (Jpn.); (-V-), Hatakinumochi (Jpn.). lated from thyme, another Perilla plant, and two of these (8,9)
showed activities comparable to BHT.99-100 Two flavonoids of
the same origin (10,11) were also antioxidative.101
similar studies also indicated that oregano, allspice, and others Capsicin (12) and dihydrocapsicin, hot-tasting components
were effective in petroleum ether soluble fractions, and red of Capsicum, are antioxidative but not suitable for general food
pepper, basil, etc. in petroleum insoluble fractions, and rose- use. However, a new antioxidative without hot taste (13) has
mary, sage, and mace in both fractions, and that petroleum been isolated from Capsicum frutescens by Nakatani.102
o.ia
(a) f 40-
f
n
n
in
0.16
- /
30-
a 0.14 •
A'l
9 '
o / ,'ty
p A/ 20-
3
< 0.12
/,p / s
M
o
1-
0.10
0.095
OO9
1.0 2.0 1.0 2.0
Y-Ray Irradiation Do»« (M rads)

Y-Ray ln»dlatlon Dot* (M radi)
FIGURE 10. Effects of-y-ray irradiation on TBA values of Kusabue and Katakutara rice seeds irradiated
before and after dehulling. (a) TBA value; (b) ESR signal intensity.80 - • - , Dehulled Kusabue; -O-,
dehulled Katakutara; -A-, Kusabue with hull; - • - , Katakutara with hull.

(A)
Hull KU •TBLDH
1
Hull KA 1
Br+ Germ KU 1
Br+ Germ KA 1 isovitexin.
Grain KU
CONTROL
Grain KA | BHA
Ct-Tocophero! a-TOCOPHEROL 1
1
1 i
2 1
t i l l i
3
0 25 50 75 100
4 1
INHIBmON OF LIPID PEROXIDATION (%) S1 '
6
(B)
; i
Hull KU 8
J
9
Hull KA . 1
10
Br+Germ KU 1•
Br+Germ KA
Grain KU 1^ •
Grain KA
11
Cl-Tocopherol
0 20 4 0 6 0 8 0 100
UPtO PEROXIDATION (%)
J
0 25 ite-
50 75 100
INHIBITION OF LIPID PEROXIDATION (%) RGURE 12. Antioxidative activities of HPLC separated subfractions of
Katakutara rice hull MeOH-H2O (50:50) fraction and structure of subtraction
ll-(iii) identified by instrumental analyses as isovitexin.83
FIGURE 1 1 . Antioxidative activities of (A) CHCl3-Me0H and (B)
Me0H-H 2 0 extracts of different fraction (hull, bran and germ, and
grain fractions) of Kusabue (KU) and Katakutara (KA) rice seeds.77
D. Flavonoids and Tea Catechins
Antioxidative activities of (A) CHCl3-Me0H and (B) MeOH-H2O ex-
tracts of different fractions (hull, bran and germ, and grain fractions) Antioxidative activities of phenolic flavonoids in plants have
of Kusabue (KU) and Katakutara (KA) rice seeds. long been known and studied. Quercetin is representative and
widely distributed. Many studies have been done on the struc-
Although black pepper was reported to not be significantly ture-activity relationship of quercetin by methylation of OH
antioxidative, five antioxidative phenolic acid amides were groups (Figure 14).106-109 They indicated that 3' and 4' OH,
isolated from a weakly acidic fraction of its extract.103 Ferulic especially the latter one, in the B ring plays the most important
acid amide of tyramine (14) and a piperine-related compound role in the activity and that 3 and 5 OH are also important.
with an open methylenedioxy ring (15) among these are taste- However, modification of 7 OH only slightly reduced the ac-
less and odorless and showed stronger activity than tocopherol tivity, while the addition of an OH group at the 8 position of
in a water-ethanol system. These are essentially fat-soluble. the A ring enhances the activity as in gossypetin and herba-
Recently, several tasteless and antioxidative constituents have cetin.109 The 2 to 3 double bond is also important for conju-
been isolated from turmeric (Curcuma longa L.), and two of gation of the A and B rings since its hydrogenation resulted
them had the same skeleton structure as curcumin, the yellow in significant decrease in activity. Examination of the metal-
pigment of turmeric (16,17).104 Tetrahydro curcumin (18) is chelating power of quercetin showed that 3 OH or 5 OH with
colorless, heat-resistant, and antioxidative.105 These com- a 4 keto group is the most powerful chelating group, and that
pounds have phenol groups and have a p-diketone group; the the 3 ' and 4 ' groups in the B-ring have only weak Cu-chelating
latter is also found in the antioxidative fraction of Eucalyptus activity.108 Flavonoids have strong synergistic action with citric
leaf wax.134 acid and melanoidin.109
Antioxidative flavonoids have also been isolated from rose- Also often studied are the antioxidants in soybean, mainly
mary and other spices. the isoflavones genistein, daidzein, and glycitein, which are
1990 285
Critical Reviews In
Rosemary
OH
OR
HO. RO,
l\" CH,
H 6 OR'
R, R =H
(1) Carnosol (2) Rosraanol (7 a-) (3) Isorosmanol

(4) epirosmanol (7 ^-)
Oregano
CH.CH,
Capsium Turmeric
.OCH,
.H »<KO
(12) (16)
yOCH:
OVOH
(13) (17)
Pepper
H3CO
HO-CO
(18)
(14)
FIGURE 13. Antioxidants in spices (for explanation of number in parentheses see text).

OH
HO
Quercetin
HO.
HO
Genistein Daidzein
OH OH
r
HO 6
Butein Licochalcone B
OH OH
OCH-
HO
HO HO
Naringenin Diosmetin Morin
OCHJ
OG!
0G1
= gtucosjrl
Procyanidin B-l Malvinin-3,5-diglucoside

FIGURE 14. Antioxidative flavonoids.
1990 287
Critical Reviews In
active in this order, but their activities are weaker than quer- have been focused on recently. Its effects are assumed to be
cetin, according to Pratt.110 The oil of Temphe, an Indonesian due to the SOD-like activity of quercetin and other components
fermented soybean food, is less prone to oxidation than soybean to scavenge superoxide anion radical.
oil, and it was demonstrated that the stability is due to the On the other hand, the redox active flavonoids such as myr-
antioxidative activities of isoflavones from isoflavone gluco- icetin and quercetin have been shown to produce hydroxy rad-
sides in soybean,111 and that the products of the Maillard re- icals and their semiquinone radicals during metal-catalyzed
action may be involved.112. Other antioxidants, caffeic acid, autoxidation.124
chlorogenic acid, ferulic acid, and others, have also been iso- Recent studies have indicated strong mutagenicity of fla-
lated from soybean.110 vonoids, especially quercetin, in Ames bacterial assay and
Structure-antioxidative activity relationships of flavones, others, but no carcinogenicity in animal tests, and, in contrast,
flavanones, chalcones, phenolic acids and esters, and dihy- antimutagenic activity for catechins. These studies prompted
drochalcones in a lard system have been studied by Dziedzici reexamination of the antioxidative activity of these compounds.
and Hudson.112"118 Among the isoflavones, genistein and pru- From tea leaves, Hara and co-workers isolated ( —)-epica-
netin were very active, 4', 6, 7-trihydroxy isoflavone margin- techin (EC), (-)-epigallocatechin (EGC), ( - )-epicatechin
ally so, and the others were inactive. Pronounced synergistic gallate (ECg), and ( - )-epigallacatechin gallate (EGCg) hom-
effect was observed with these isoflavones and ologues in pure form by HPLC and examined their antioxidant
phosphatidylethanolamine.'I7 activities125 (Figure 15). They showed activities stronger than

3,4-Dihydroxy chalcones, such as butein ( 2 \ 4 ' , 3, 4-OH) BHA or dl-tocopherol in a lard autoxidation system; the order
and okanin (2', 3 ' , 4', 3, 4-OH), have been shown to be was EC < ECg < EGC < EGCg on molar bases. Strong
particularly effective antioxidants in a lard system and more synergistic effect of EGCg was seen with ascorbic acid and a-
effective than the corresponding flavones. The important role tocopherol, and also with citric acid and tartaric acid, but not
of the 3,4 OH groups in the B ring was emphasized to give with amino acids.
an extended resonance form of free radicals. Although the Recently, the scavenging effects of green tea extracts and
reason is not yet clear, it is interesting that dihydrochalcones other natural antioxidants on active oxygen radicals have been
were clearly more effective as an antioxidant than the corre- studied by Wenjuan et al.126 using a spin trapping method. In
sponding chalcones.118 stimulated polymorphonuclear leukocytes system, water ex-
Among several flavonoids and related compounds isolated tract fraction of green tea and green tea polyphenols showed
from the licorice root, licochalchone B and A showed the most most strong scavenging activity, followed by ascorbic acid,
effective inhibition on the 5-Iipoxygenase dependent peroxi- rosemary antioxidant, and others.126
dation in arachidonate metabolism as well as on radical scav-
enging effect of the l,l-diphenyl-2-picrylhydrazil(DPPH) E. Tannins
radical.119 Tannins are widely distributed in barks and nuts, sometimes
Two procyanidine dimers having antioxidative activity higher reaching several tens of weight percent. Although their phys-
than a-tocopherol in a linoleic acid-p-carotene-water system iological significance is not clear, they are assumed to be an-
have been isolated from azuki (red bean).120 Reactivity of these tioxidative from their polyphenol structures; esters of gallic
dimers with the DPPH radical was shown to be faster than that acid, the main structure of the tannins, are in practical use as
of a-tocopherol. food antioxidants.
Antioxidative activity is also known in anthocyanin pigment Their activity, seen either in a methyl linoleate autoxidation
of a wild grape in Japan. The pigment has been identified as system or a rat liver microsome system,127 is attributed to the
malvidin-3,5-diglucoside, and the activity was stronger with stability of their radical form (Figure 16), which acts as a good
its aglycone.121 radical scavenger. This is supported by the observation of ESR
Recently, mechanistical studies on antioxidative activity of signals of tannins, which persist longer than those of low-
flavonoids have been conducted using spin trapping and other molecular-weight phenols.128 Such action may be related to the
advanced techniques; Robak and Gryglewski122 showed that inhibiting action on lipoxygenase in arachidonic acid metab-
flavonoids can effectively scavenge superoxide anion radicals olism,129 and on liver injury in rats fed peroxidized oil.130
and the activity was on the order quercetin > myricetin > Su and co-workers131 screened 230 Taiwanese traditional
rutinin. Husain et al.123 examined reactivity with the OH radical medicinal plants for antioxidative activity in relation to their
generated in a hydrogen peroxide-UV system, and flavonoids medical effects and found 22 plants with activity stronger than
were shown as effective scavengers on the order myricetin > that of a-tocopherol. Antioxidants in Osbeckia chinensis L.,
quercetin > rhamnetin > morin > diosmetin > naringenin which was strongly active and did not contain a-tocopherol,
and others, and the activity increased with the number of HO were extracted and identified.132 The water-soluble tannins
groups in the B-ring. shown in Figure 17 were identified as the main antioxidative
Medicinal applications of the extract of ginko tree leaves constituents, and kampferol, quercetin, and its three glucosides

as well as ellagic acid, gallic acid, and methyl gallate were

also obtained as other antioxidative constituents.132 The order
of the activity in three test systems were gallic acid < a-
tocopherol < methyl gallate < (4) < (3) < (5) = (6) < (2)
< (1) in the linoleic acid autoxidation system; a-tocopherol <
gallic acid < methyl gallate < (4) < (3) < (5) = (6) = ellagic
acid < (2) < (1) in the rat erythrocyte membrane ghost cell
EC ; R,=H R 2 =H system; and ellagic acid < (4) < gallic acid < (3) = (5) =
(6) < methyl gallate < (2) < (1) = a-tocopherol in the rat
EGC; R, = OH R2 = H liver microsome system. These results indicated high activity
of (1), (2), and ellagic acid in biological systems.
ECg; R1= H R2= -0C
A furan derivative, osbekic acid, also isolated from the same
plant, while not antioxidative itself, acted as a potent synergist
with a-tocopherol, methyl gallate, and others. The mechanism
of its action is not yet clear.133
EGCg; R, =
-OC
F. Leaf Wax
Many Eucalyptus plants with a high content of essential oils
have a thick layer of leaf wax, which was examined for an-
tioxidative activity.134 Among many active leaf waxes found,
that of Eucalyptus globulus, much of which is found in Japan,
was used for isolation of the active components, and n-tritria-
200.- contan-16, 18 dione and their homologues were identified as
new P-diketone type antioxidants (Figure 18). Both the P-
diketone structure and the presence of two long alkyl chains
were required for the antioxidative activity.135 As described
previously, curcumin and its tetrahydro derivative were very
effective antioxidants and have a p-diketone structure.105 Re-
> 100- cently, new p-diketone type antioxidants, H-pentacosane 8, 10
o dione and others, were also identified as strong antioxidative
constituents in stigma lipids of tobacco.136 Chelation may not
be the cause of the activity in these P-diketone compounds and
their mechanism is not yet clear.
Antioxidants have been also sought in leaf waxes of Japanese
wild plants. Some of the active wax contained a-tocopherol,
and one from a kind of cherry tree was found to contain a
strongly antioxidative phenolic compound.37
FIGURE 15. Antioxidative activity of tea catechins. (A) Structural formula of four
catechins, (B) antioxidative activity of four catechins by AOM at 97.8°C on lard.125
• , None; A, dl-a-toc. 200 ppm; ^ , BHA 50 ppm; O , ECg 50 ppm; • , EGCg 20 G. Porphyrin-Related Substances
ppm; O , EC 50 ppm; D , EGC 20 ppm. Heme-related substances such as hemoglobin are sometimes
known to accelerate the autoxidation of lipids, but Matsushita
HO OH and Iwami138 postulated that the prooxidant activity may be
attributed to the action of the iron atom in their molecule, and
HO
porphyrin compounds themselves may possess antioxidative
activity based on the fact that their highest filled molecular
energy level (HJ^MO; Pullman and Pullman) is lower than that
of a-tocopherol and ascorbic acid. In their examination, he*
matin was found to promote autoxidation, but billirubin, Cu
chlorophylin, pheophytin, and others exhibited a suppressive
effect. Stacker and co-workers40 showed the strong antioxi-
OH dative activity of billirubin, the final decomposition product
of heme in vivo, especially under low oxygen partial pressure
FIGURE 16. Free radical structures of tannins.128 of in vivo conditions. Billirubin exhibited stronger activity in
1990 289
Critical Reviews In
CH,OH
H.OH
x N
HOC ;—(v />OH HO(' > ^ '>0H
HO OH HOÔH HO~~OH HO OH
CHjOH
' ÔH
HO
^ H
co rvJ>\
ofrH.oH
OH
HO OH HO OH HO OH HO OH
2 4
FIGURE 17. Tannin antioxidants from Osbeckia chinensis L. 132
ribosome membrane than in homogenous solution, suggesting where, 143 only the recent information regarding their
the importance of its role in biological systems. antioxidative activity is discussed below.
Chlorophyll and related products are known to act as proox- The antioxidative activity of these products was first dis-
idants in lipid autoxidation based on their photosensitizing ef- covered through the observation of an increase in stability to
fect.1391 Endo and co-workers140141 showed that chlorophyll b autoxidation by heating powdered milk for a short period of
has about twice the prooxidant activity of chlorophyll a, and time.144 The effect of a combination of reactants, pH, heating,
also that the decomposition products of chlorophyll, pheophy- and other factors have been examined.145 It is generally be-
tin, and especially pheophorbide are more active prooxidants lieved that the activity increases with browning and originates
than chlorophyll b. in melanoidin, but because the nature of melanoidin is far from
However, it was demonstrated that chlorophyll could act as being clear it can only be presumed that its reductone structure
an effective antioxidant under dark conditions, presumably by is the source of activity.
its hydrogen-donating action. Nishibori and Namiki142 noted Recent studies by Yamaguchi et al.146 using fractionation by
the strong antioxidative nature of the lipid fraction of seaweeds dialysis and HPLC showed an active fraction with a molecular
and isolated pheophy tin a from aonori (a kind of green Japanese weight of approximately 5000; Lingnert and Eriksson147 found
seaweed) as the effective constituent that is a strong antioxi- activity in an ESR-active fraction, but this fraction was not
dative in the dark. made homogeneous and the result is inconclusive.
Strong antioxidative activities were also found in the systems
H. Maillard Reaction Products of low-molecular-weight sugars and dicarbonyl compounds such
Maillard reaction, which is highly important to food quality, as methylglyoxal, glyceraldehyde, dihydroxyaceton,148 and de-
is also related to antioxidative action, mutagenicity, and an- hydroascorbic acid149 with amino acids. Attempts to isolate and
timutagenicity. Since these subjects have, been reviewed else- identify the active reaction products have been made by solvent

Induction period (day) ulate biological conditions were performed to obtain fore-
5 I? 15 20 knowledge about their efficacy in biological systems.
Table 6 shows the results of one example of such experiments
CHj-t-CHj-6-CHj on sesaminol and other components isolated from sesame seed
*«etyl acelone
oil. These lignan phenols showed high activities roughly equiv-
alent to that of tocopherol in both the erythrocyte membrane
system and the rat liver microsome system.152 Sesaminol also
Syncarpic Kin
showed suppressive action on lipid peroxidation of human dip-
loid fibroblasts induced by tert-butyl peroxide.153 The results
j CH. of similar in vitro experiments on natural phenolic antioxidants
Oipiviloylmtllunt'
are summarized in Table 7.154 It was suggested that the strong
suppressive effect of ellagic acid is due to its inhibition of
perferryl ion-dependent initiation of peroxidation. Ellagic acid
shows a suppressive effect stronger than that of tocopherol on
peroxidation in a microsome system, as well as on peroxidation
Curcumin
of linoleic acid by POV measurement; however, the working
mechanism is not explained by its reactivity with superoxide,

•OH radical, and other species.
Table 6
l6-Hydroiy-l3-trllrixonUnant (S-2AI Relative Antioxidant Activity of Sesame Lignans
using Rat Liver Microsome and Erythrocyte Ghost
Systems 152
ADP-
BHA(200jjg) L Fe 2+ ADP-Fe>+/EDTA-Fe3+ Erythrocyte
/NADPH /NADPH ghost
Control Control 100 100 100

PI 14.9 13.2 20.2
Sesamolinol 4.6 6.3 24.7
FIGURE 18. Antioxidative activity of p-diketone derivative (Thiocya- Sesaminol . 8.6 10.3 22.8
nate method).135 Pinoresinol 17.2 14.4 18.4
Sesamol 24.1 19.0 19.0
extraction of the reaction of a dehydroascorbic acid-tryptophan ct-TocopheroI 9.2 19.0 24.7
mixture at an early stage. One of the active products was
identified as a new equimolar condensation compound of each
X. ANTIOXIDATIVE VS. ANTIMUTAGENIC
material.150
ACTIVITY
The activity of Maillard products is not especially high, but
is enhanced by tocopherol and other agents. Involvement of
With the establishment of microbial mutagenicity tests such
metal inclusion activity of melanoidin is suggested.
as the Ames test155 and the Rec-assay156 as routine procedures,
Yamaguchi151 tried to oxidize antioxidative melanoidin by
large numbers of mutagens have been found in food and en-
ozone or some microbes for the purpose of decolorization.
vironmental systems.157 The mutagens found in these microbial
Considerable decoloration was attained with only insignificant
tests are not always carcinogenic, but most known carcinogens
decrease in the antioxidative activity. Decrease in C = C bonds
have been shown to be strongly active in these tests.158 Mu-
and increase in C = O bonds by these oxidations were found
tagens in foods, especially those found in roasted foods and
by IR analysis, which is an interest in considering structure-
showing extremely strong mutagenicities,159 have been the cause
antioxidative activity relationships.
of much concern by the geneal public.
The present theories of mutagenesis and carcinogenesis have
IX. ACTION OF ANTIOXIDANTS IN MODEL defined the initiation and promotion steps in these processes.
BIOLOGICAL SYSTEMS Initiation is the development of primary damage on DNA caused
by many agents and mutagens, and promotion is the malignant
As described in Section VI, prior to animal experiments, in transformation of the damaged cells by secondary external fac-
vitro tests of antioxidants of natural and food origins that sim- tors, leading to mutagenesis or carcinogenesis, as shown in
1990 291
Critical Reviews In
Table 7 metabolic processes that should normally inactivate and dispose

Inhibition of Lipid Peroxidation in The Rat Liver of the external agent; the binding action of the metabolically
Microsome System by Polyphenols (A), and by produced epoxide derivatives of benzo(a)pyrene to DNA bases
Ellagic Acid and Two Derivatives (B)154 is well known. On the other hand, there are many other mod-
ifying factors in the process, such as excretion of toxic agents
ica by glutathione and others, aided by enzyme systems, and repair
ADP-Fe2*/ of the damaged DNA by specific enzyme systems.
A. Compound NADPH ADP-Fe3+/EDTA-Fe3+/NADPH Recent studies have shown the presence of a number of
agents that inhibit mutagenic action in food. The mode of action
Ellagic acid 20 ± 1 23 ± 2
of these antimutagens is diversified, considering the complexity
p-Coumaric acid 330 ± 8 >100
Vanilic acid 400 ± 6 >100 of the mutagenic processes. Some may suppress the formation
Salycilic acid 460 ± 5 >100 of mutagens, some may directly inactivate the mutagens, and
Ferulic acid >500 >100 some may inhibit the activation of the mutagens. Kada, a
Gallic acid >500 8.0 ± 0.3 pioneer in this field, called these "desmutagens", and called
Gallic acid methyl ester >500 >100
those antimutagens that work in later stages, e.g., DNA repair
Chlorogenic acid >500 67 ± 4
Caffeic acid 340 ± 8 80 ± 6
and promotion stages, "bio-antimutagens".160161
Syringic acid >500 >100 Referring back to peroxidation and antioxidation, it is highly
a-Tocopherol 320 ± 3 0.80 ± 0.02 probable that the active oxygens,162 active free radicals, and
Propyl gallate >500 20 ± 3 carbonyl compounds163 induced by peroxidation are responsible
for part of the mutagenic initiation and promotion.164 This is
ic M -
supported by epidemiological studies in many countries that
ADP- ADP-FeW indicate a positive correlation between the incidence of intes-
Fe2*/ EDTA-Fe3*/
B. Compound NADPH NADPH Adriamycin tinal and lung cancer and the intake of neutral fat.165 Carcin-
ogenesis of mouse by DMBA is known to be enhanced by
ot-Tocopherol >100 0.80 ± 0.02 5.5 ± 0.2 intake of large quantities of unsaturated fats.166 Also, in some
Propyl gallate >100 20 ± 3 0.30 ± 0.02 instances, effective antioxidants have been found to suppress
Ellagic acid 20 ± 1 23 ± 2 0.10 ± 0.01 the mutagenesis,167 and in some cases to extend the lifespan
Hexahydroxydiphenic >100 >100 7.0 ± 0.5
acid
of animals.168
Ellagic acid tetraacetate >100 >100 31 ± 3 Although these relationships are not clear-cut in many spe-
cific cases, it is useful to introduce the results of recent studies
Note: 'ICs, = concentration (\LM for 50% inhibition of lipid peroxidation in in this area.
model systems. Reported values are mean ± SD (« = 3).
A. Desmutagens
Figure 19.160 In the initiation process, the agent that works on Phenolic antioxidants and other agents have been tested for
DNA may be the agent itself, but may also be the product of suppressive effect on mutagenesis. For the formation of potent
Fornation
v
I Hutagenl v
Lie IL
Metabolic
activation!C
Genetic
toxicity
Cancer
Mutant
Aging
Recovery
FIGURE 19. Schematic actions of desmutagens and bio-antimutagens.160

mutagen nitrosamines, the suppressive action of ascorbic acid 100

is well known.169-170
Phenols react more rapidly with nitrosation agents than
amines, which results in a prevention or sometimes a catalytic
promotion of nitrosation of amines.171175 The mode of modi-
fication influenced greatly by concentration of materials, pH,
and other reaction conditions; for example, sesamol, a sesame
oil antioxidant, inhibited the nitrosamine formation of mor-
pholin as effective as ascorbic acid at pH in neutral, but, rather,
promoted the formation in acidic condition.173 1,2- and 1,4-
diphenols such as chlorogenic acid and hydroquinone were a
very effective inhibitor for the nitrosation, probably due to
their reducing activity of N2 O3,175 while eugenol was less
effective and vanillin acted rather enhancer.176-177
Many studies have been conducted on suppressing effects
of BHA on mutagenesis and carcinogenesis. It was shown that
1.0 2.0 3.0

BHA acted as an effective inhibitor on the formation of nitro- ELLAGIC ACIDtnmol)
samine,178 and the formation of mutagens in roasting of food,179
but it also enhanced the activities of enzyme systems in the
detoxication processes of mutagens and carcinogens, and also
induced some alteration of the cytochrome p-450 system, re-
sulting in metabolism of carcinogens to less toxic
metabolites.180181
Wood and co-workers182 revealed the in vitro inactivation
of the metabolic intermediate of benzo(a)pyrene by the an-
tioxidative phenols ferulic acid, caffeic acid, chlorogenic acid,
and ellagic acid. Benzo(a)pyrene, a representative carcinogenic
polycyclic aromatic hydrocarbon, is found in exhausts, tobacco 100 200 300 400 500
smoke, and in food, and its powerful carcinogenicity is attrib- COMPOUND (nmol)
uted to its metabolic activation involving hydroxylation and
epoxide formation at the 7,8 and 9,10 positions and subsequent FIGURE 20. Effect of ferulic, caffeic, chlorogenic, and ellagic acids
binding with DNA. In their experiments, the mutagenicity of on the mutagenicity of B(a)P7,8-dioI-9,10-epoxide-2 in strain TA100
of 5. typhimurium.1*2
the metabolite toward Salmonella typhymurium or Chinese
hamster V79 cells was markedly decreased by these agents,
especially ellagenic acid, a strong antioxidant (Figure 20). They also reported by Okuda et al.186 Inactivation by chemical bind-
also assumed that ellagic acid molecules in solution easily ing, as seen for ellagic acid, appears to be the mode of action
orient themselves parallel to the plane of the epoxy metabolite in the tannin.
and bind with it with the opening of the epoxide ring (Figure Strong inhibitory activities on the mutagenicity of Trp-P-2
21).183 were also observed in the water extracts of various herbs,
Hung et al. 1 8 4 tested flavonoids for inactivation of especially with bay, berfamont, English lavender, Florence
benzo(a)pyrene activated by rat liver microsome, and found demel, peppermint, thyme, and others.187
myricetin, robinetin, and luteolin as active agents. Hydroxyl Pashin and Bakhinova188 also reported suppressive action of
groups were required in the molecules, and it was assumed phenols toward mutagenesis of Chinese hamster V79 cells in-
that their reaction with the metabolite causes the inactivation. duced by Benzo(a)pyrene or by "y-radiation, and a linear re-
They also reported on the inhibition of the mutagenicity of lation with the phenol molecules, besides the structural factors.
B(a)P 7,8-diol-9,10-epoxy-2 toward TA 100 of the Ames test
system by tannic acid and hydroxylated anthraquinones and B. Bio-Antimutagens
showed that tannic acid and 2,6-dihydroxyanthraquinone ex- After the first finding of bio-antimutagenic effect on cob-
hibited a strong inhibitory activity and digallic acid and m- altous ion against MNNG-induced mutation in the strain of
digallic acid, major components of tannic acid, possessed only WP2 of E. coli B/r, Kada et al. have carried out a systematic
less than 1% of the activity of tannic acid.185 Inhibitory effect screening for natural bio-antimutagens in various components
of tannins, especially that of geranniin from Geranium thun- of plants and foods by means of microbial assays against spon-
gergii on mutagenicity of B(a)P diol epoxide and Trp-P-2, was taneous and radiation or chemically induced mutation. They
1990 293
Critical Reviews In
These data seem promising for the application of antioxi-

dants to inhibit the promotion stage of mutagenesis and
carcinogenesis.193
Hara and co-workers194 recognized suppression of growth
of Erlich-Sarcoma 180-, and 20 MC-transplanted tumors in
mouse by oral administration of green tea extract. Ito and co-
workers195 also reported potent suppression of aflatoxin B,-
induced chromosome aberration in rat bone marrow cells by
administration of hot water extract from green tea at 24 h before
the aflatoxin injection, but no effect at 2 h before or after
injection.
Agrimoniin, a tannin isolated from Agrimonia pilosa Ledeb
and Agrimonia japonica (M1Q) Koidz, showed effective an-
titumor activity by intraperitoneal administration to mice once
at 4 d before the intraperitoneal incubation of mouse mammary
carcinoma MM2 cells.J9S
Cheng et al. 197198 showed the antimutagenic action of green

tea extract on mutagenesis of Ames TA 98 strain induced by
benzo(a)pyrene, aflatoxin B,, and extract of fried fish on sister
chromatid exchange and chromosome aberration in Chinese
hamster cell induced by aflatoxin B ^ and B 2 , and on the increase
of ornithin decarboxylase by promotive effect of 12-O-tetra-
decanoylphorbol-13-acetate (TPA). In addition, they reported
HO
suppression of mouse skin cancer, induced by DMBA and skin
application of promoter TPA, by administration of green tea
FIGURE 21. Addition compound of benzo(a)pyrene diol epoxide and ellagic extract. Yoshizawa et al.199 showed the inhibitory effect of
acid.183 ( - ) — epigallocatechin gallate (EGCg) on promoting action of
teleocidin to tumor formation by DMBA, and the relating strong
have found that Japanese green tea extract showed the highest inhibitory effect on the activation of protein kinase C by te-
bio-mutagenic activity among several hundred specimens, and leocidin. A significant protective action of green tea polyphe-
chemically showed that the active factor is epigallocatechin nols against two stage skin tumorigenicity by DMBA and TPA
gallate.189 was also reported by Wang et al.,200 in addition to the antiin-
Simoi and co-workers190191 treated Escherichia coli B/r cells itiating effect of the polyphenols on the skin tumorigenicity
with tannins after induction of mutagenesis by ultraviolet ir- induced by benzo(a)pyrene. A possible mechanism of the an-
radiation. ( — )—Epigallocatechin gallate and ( —) —epicate- tipromoter activity of green tea polyphenols has been proposed
chin gallate reduced the mutagenicity by 70%, but chlorogenic by Ruch et al., in relation to their antioxidative activity to
acid, pafferic acid, D — ( + ) — catechin, and quercetin had no present oxygen cytotoxicity and inhibition of intercellular com-
effect, suggesting the requirement of a trihydroxyphenol struc- munication caused by. the TPA.201
ture for the effect. Since no effect of tannins was observed for The data being accumulated indicate antipromoter action of
the E. coli B/r strain deficient in scission repair enzyme, the tannins and other phenolic antioxidants, providing reason to
antimutagenic action of tannins was assumed to be believe that continued research will take favorable directions.
bioantimutagenic.
Phorbol 12-myristate-13-acetate (PMA) is a well-known pro-
moter of mouse skin cancer, and its action accompanies in- XI. CONCLUDING REMARKS
duction of ornithine decarboxylase (ODC), hyperplasmia, and
inflammation, which symptoms appear to be related to the The social need for safe and available food antioxidants
increase of active oxygen and promotion of peroxidation pro- continues to exist, despite technological advancement in food
duced by inhibition of SOD and catalase activities. This sug- processing and distribution, especially in countries that depend
gests a possibility for the action of antioxidants, and, in fact, heavily on fresh foods and in less-developed areas.
BHA and BHT showed marked inhibition of PMA-induced Although BHA and BHT, antioxidants currently in wide use
tumor promotion in mouse skin as reported by Kozumbo and are considered safe, extensive use will have to be curtailed in
Cerutti.192 BHT, along with SOD and catalase, also showed the future, given the recent trend against synthetic food ad-
inhibitive effect on poly (ADP)-ribose accumulation of human ditives. Looking at antioxidants of natural origin, some have
and mouse fibroblast nuclear protein induced by PMA. been already proven in model systems to be effective as BHA

and BHT, and those from established food, e.g., sesame, are ACKNOWLEDGMENTS
expected to be safe as food additives. However, the devel-
opment of antioxidants of natural origin comparable in prac- The author expresses gratitude to Dr. Keiichi Tsuji for his
ticability to BHA will not be easy, especially with respect to excellent advice concerning both the content and language of
applicability to variety of foods, stability, solubility, ease of this review. Thanks are also due to Dr. Toshihiko Osawa for
manufacture, and cost, etc. helpful discussions.
Behind this difficulty lies the fact that most natural antiox-
idants seldom work singly by themselves, but become effective
as parts of antioxidative systems by synergistic action. This
often results in failure to obtain a single potent antioxidant by
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Critical Reviews in Food Science and Nutrition

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chemical changes. The latter is represented by enzymatic and

Triplet Singlet Singlet

FIGURE 1. Physical properties and electron configuration of oxygen molecules.18

274 Volume 29, Issue 4

'Sen + 0 , (>S,-) > Sen + 'O, (XJ, o r

FIGURE 2. Singlet oxygen. Formation by photosensitization and ene reaction.

Cytochrome oxidase complex

Table 1 covery systems; for example, by repair enzymes, which, on

276 Volume 29, Issue 4

A=-(CH2)7 COOH;B = -(CH2)4 CH3;I=9-trans, cis-LOOH; II =13-

NADPH- Cyt./»- 450

NADPH- Cyt. i"- Cytochrome p-450

IH- 't DPF

FIGURE 5. Schematic of the proposed mechanisms for lipid peroxidation.22

278 Volume 29, Issue 4

Promotion Suppression Peroxide value (POV)

VI. EVALUATION OF ANTIOXIDANTS IN Plant

280 Volume 29, Issue 4

RELATED ANTIOXIDANTS saminol, which is found in high content in purified unroasted

Syringic acid Ferulic acid Sesamol dimer

FIGURE 7. Sesame lignans (A) and antioxidants (B) (* only in S. angolense).*

B. Rice germination potential of rice seed may possibly be related to

282 Volume 29, Issue 4

100 ether extracts of rosemary and sage were as effective as

Y-Ray Irradiation Do»« (M rads)

284 Volume 29, Issue 4

(1) Carnosol (2) Rosraanol (7 a-) (3) Isorosmanol

286 Volume 29, Issue 4

Naringenin Diosmetin Morin

Procyanidin B-l Malvinin-3,5-diglucoside

phosphatidylethanolamine.'I7 activities125 (Figure 15). They showed activities stronger than

288 Volume 29, Issue 4

as well as ellagic acid, gallic acid, and methyl gallate were

FIGURE 17. Tannin antioxidants from Osbeckia chinensis L. 132

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mechanism is not explained by its reactivity with superoxide,

Control Control 100 100 100

Table 7 metabolic processes that should normally inactivate and dispose

FIGURE 19. Schematic actions of desmutagens and bio-antimutagens.160

292 Volume 29, Issue 4

mutagen nitrosamines, the suppressive action of ascorbic acid 100

1.0 2.0 3.0

These data seem promising for the application of antioxi-

Cheng et al. 197198 showed the antimutagenic action of green

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298 Volume 29, Issue 4

The pyrogallol related compounds reduce UV-induced mutations in

300 Volume 29, Issue 4

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