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Critical Reviews in Food Science and Nutrition
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Tannins and Human Health: A Review
King-Thom Chung , Tit Yee Wong , Cheng-I Wei , Yao-Wen Huang & Yuan Lin
To cite this article: King-Thom Chung , Tit Yee Wong , Cheng-I Wei , Yao-Wen Huang & Yuan Lin
(1998) Tannins and Human Health: A Review, Critical Reviews in Food Science and Nutrition,
38:6, 421-464, DOI: 10.1080/10408699891274273
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Critical Reviews in Food Science and Nutrition, 38(6):421–464 (1998)
Tannins and Human Health: A Review

King-Thom Chung,1,* Tit Yee Wong,1 Cheng-I Wei,2 Yao-Wen Huang,3
and Yuan Lin 4
1
Department of Microbiology and Molecular Cell Sciences, The University of Memphis,
Memphis, TN 38152; 2Food Science and Human Nutrition Department, University of Florida,
Gainesville, FL 32611–0370; 3Department of Food Science and Technology, University of
Georgia, Athens, GA 30602–7610; 4Center of Biologics Evaluation and Research, Food and
Drug Administration, Rockville, MD 20852
* Corresponding author.
Referee: Dr. Michael G. Johnson, Department of Food Science, University of Arkansas, Fayetteville, AR
72703
ABSTRACT: Tannins (commonly referred to as tannic acid) are water-soluble polyphenols that
are present in many plant foods. They have been reported to be responsible for decreases in feed
intake, growth rate, feed efficiency, net metabolizable energy, and protein digestibility in experi-
mental animals. Therefore, foods rich in tannins are considered to be of low nutritional value.
However, recent findings indicate that the major effect of tannins was not due to their inhibition
on food consumption or digestion but rather the decreased efficiency in converting the absorbed
nutrients to new body substances. Incidences of certain cancers, such as esophageal cancer, have
been reported to be related to consumption of tannins-rich foods such as betel nuts and herbal
teas, suggesting that tannins might be carcinogenic. However, other reports indicated that the
carcinogenic acitivity of tannins might be related to components associated with tannins rather
than tannins themselves. Interestingly, many reports indicated negative association between tea
consumption and incidences of cancers. Tea polyphenols and many tannin components were
suggested to be anticarcinogenic. Many tannin molecules have also been shown to reduce the
mutagenic activity of a number of mutagens. Many carcinogens and/or mutagens produce
oxygen-free radicals for interaction with cellular macromolecules. The anticarcinogenic and
antimutagenic potentials of tannins may be related to their antioxidative property, which is
important in protecting cellular oxidative damage, including lipid peroxidaton. The generation of
superoxide radicals was reported to be inhibited by tannins and related compounds. The antimi-
crobial activities of tannins are well documented. The growth of many fungi, yeasts, bacteria, and
viruses was inhibited by tannins. We have also found that tannic acid and propyl gallate, but not
gallic acid, were inhibitory to foodborne bacteria, aquatic bacteria, and off-flavor-producing
microorganisms. Their antimicrobial properties seemed to be associated with the hydrolysis of
ester linkage between gallic acid and polyols hydrolyzed after ripening of many edible fruits.
Tannins in these fruits thus serve as a natural defense mechanism against microbial infections.
The antimicrobial property of tannic acid can also be used in food processing to increase the
shelf-life of certain foods, such as catfish fillets. Tannins have also been reported to exert other
physiological effects, such as to accelerate blood clotting, reduce blood pressure, decrease the
serum lipid level, produce liver necrosis, and modulate immunoresponses. The dosage and kind
of tannins are critical to these effects. The aim of this review is to summarize and analyze the vast
and sometimes conflicting literature on tannins and to provide as accurately as possible the
needed information for assessment of the overall effects of tannins on human health.
KEY WORDS: tannins, tannic acid, water soluble polyphenols, tea polyphenols.
Copyright© 1998, CRC Press LLC — Files may be downloaded for personal use only. Reproduction of this material
without the consent of the publisher is prohibited.
421
I. INTRODUCTION are esterified either partially or wholly by
gallic acid (gallotannins) or hexahydroxy-
“Tannin” was originally coined by diphenic acid (ellagitannins). After hydroly-
Seguin1 to describe the substances present in sis by acids, bases, or certain enzymes,
vegetable extracts, which are responsible for gallotannins yield glucose and gallic acids.
converting animal skin into leather. In plant The hexahydroxydiphenic acid of ellagi-
extracts, these substances exist as polyphe- tannins undergoes lactonization to produce
nols of varying molecular sizes and com- ellagic acid (Figure 1).
plexities. However, many nonpolyphenolic Important examples of gallotannins are
substances in plants also have all the chemi- Chinese tannin (tannic acid), Turkish tannin,
cal properties of tannin but have not been Tara tannin, Acer tannin, and Hamamelis
tested for their ability to leather hides.2 There tannin. Chinese gallotannin extracted from
are also other substances that turn hides into nutgall contains a glucose linking through
leather but are not of plant origin. ester bonds to an average of nine to ten
Tannins have been found in a variety of molecules of gallic acid. Turkish tannin is
plants utilized as food and feed. These in- extracted from Quercus infectora; Tara tan-
clude food grains such as sorghum, millets, nin from the seed pods of Caesalpinia
barley, dry beans, faba beans, peas, carobs, spinosa; Acer tannin from the leaves of
pigeonpeas, winged beans, and other le- Korean Maple (Acer ginnala); and Hama-
gumes.3–7 Fruits such as apples, bananas, melis tannin from hazel (Hamamelis
blackberries, cranberries, dates, grapes, virginiana). The chemical structures of these
hawthornes, peaches, pears, persimmons, gallotannins are shown in Figure 2.
plums, raspberries, and strawberries also Corilagin is the simplest form of
contain an appreciable quantity of tan- ellagitannin present in Caesalpinia, Coriaria,
nins.8–14 Likewise, phenolic compounds are Terminalia chebula, Schinopsis species, and
present in wines and tea.12,15 Forages such as Eucalyptus sieberiana. Other important
crownvetch, lespedeza, lotus, sainfoin, and ellagitannins include chebulinic acid and
trefoil are also reported to contain tannins.16,17 chebulagic acid (Figure 3). Brevilagins are
Bate-Smith and Swain18 defined veg- other tannins obtained from the extracts of
etable tannin as water-soluble phenolic com- Casesalpinia brevifolia. Sweet chestnut
pounds having a molecular weight between contains dehydridigallic acid. Agarobilla
500 and 3000 D. These polyphenols contain contains tannins, which, after hydrolysis,
a large number of hydroxyl or other func- yield brevifolin carboxylic acid. These
tional groups (1 to 2 per 100 D), and there- hydrolyzable tannins occur in seed
fore are capable of forming cross-linkages pods, bark and wood, fruits, and leaves or
with proteins and other macromolecules. The galls of plants belonging to the family
low-molecular-weight phenolic compounds Leguminosae, Fabaceae, Combretaceae,
(molecular weight <500) and those of high and Anacardiaceae.20
molecular weights (molecular weight >3000) Condensed tannins are structurally more
are ineffective tanning agents.18 Vegetable complex than hydrolyzable tannins; their
tannins can also aggregate with alkaloids, complete structures are yet to be determined.
gelatin, and proteins to form precipitation. They are mainly the polymerized products
Tannins can be classified into two cat- of flavan-3-ols and flavan-3,4-diols, or a
egories: hydrolyzable and nonhydrolyzable mixture of the two. The polymers, referred
or condensed tannins.19 Hydrolyzable tannins to as “flavolans”, are popularly called con-
contain a central core of polyhydric alcohol densed tannins. Condensed tannins are widely
such as glucose, and hydroxyl groups, which distributed in fruits, vegetables, forage,
422
FIGURE 1. Hydrolyzable tannins.
423
FIGURE 2. Examples of gallotannins.
424
FIGURE 3. Examples of ellagitannins.
425
plants, cocoa, red wine, and certain food versely affecting the acceptability of such
grains, such as sorghum, finger millets, and foods.
legume. Most of the early reports related to the
Flavan-3-ols are often referred to as cat- antinutritional effects of tannins were cen-
echins. Because catechin molecules possess tered on tannic acid and other hydrolyzable
two asymmetrical carbon atoms at the tannins. However, as hydrolyzable tannins
C-2 and C-3 position, four isomers, exists. are present only in trace amounts in com-
These are (+) and (–)-catechins in which monly consumed foods, the more predomi-
2-phenyl and 3-hydroxy groups are trans. nant condensed tannins are of more concern
The (–)-epicatechin can be isolated from when discussing the antinutritional effects
cacao beans. The (–)-epigallocatechin and of tannins.
its 3-gallate are the major phenolic constitu- Ingestion of tannins may not be a nutri-
ents of green teas; (+)-gallocatechin, (+)-cat- tional problem for those people whose diets
echin, (–)-epicatechin, and its 3-gallate are include animal proteins and cereals, such as
also present. Their molecular structures are rice, wheat, corn, or barley. However, these
shown in Figure 4. compounds may exert antinutritional effects
Flavan-3,4-diols belong to the class of on people living in semiarid regions of Asia
compounds called leucoanthocyanins be- and Africa whose diets are based mainly on
cause, after heating in acidic solution, they sorghum, millets, and pulses.
polymerize into phlobaphene-like products The antinutritional and pharmacological
and produce anthocyanidines. A flavan- effects of dietary tannins and their interac-
3,4-diol molecule possesses asymmetric tions with enzymes and other proteins have
carbon atoms at C-2, C-3, and C-4; hence, been reviewed previously.4,6,7,21–23 Some of
eight isomers are present. Some structurally these effects are summarized below.
known flavan-3,4-diols are leucocyanidin, Tannins have been reported to be re-
leucopelargonidin, leucodelphinidin, guibour- sponsible for decreases in feed intake, growth
tacacidin, (+)-leucorobinetinidin, (–)-melac- rate, feed efficiency, net metabolizable en-
acidin, and (–)-teracacidin (Figure 5). ergy, and protein digestibility.4–7 Other del-
This article reviews the implications of eterious effects of tannins include damages
naturally occurring tannins for human health, to mucosal lining of gastrointestinal tract,
with emphases on their associations with alteration of excretion of certain cations, and
antinutritional, carcinogenic, anticarcino- increased excretion of proteins and essential
genic, antimutagenic, and antimicrobial ef- amino acids.24
fects. Their antimicrobial properties and Tannins at levels of 0.5 to 2% in poultry
potential applications in food processing are feed caused depressed growth and egg pro-
also discussed. duction.7,25 Similar results were observed
with chicks fed tannins at dietary levels of
0.64 to 0.84%.26 When dietary tannins were
II. TANNINS AS ANTINUTRIENTS increased to >3%, mortality occurred in test
chicks.27 Guillaume and Bellec28 reported
Tannins are often considered to be nutri- that long-term consumption of tannin-rich
tionally undesirable. Tannins form complexes faba beans caused a decrease in efficiency of
with proteins, starch, and digestive enzymes feed utilization and increased mortality for
to cause a reduction in nutritional values laying hens. Egg production by laying hens
of foods. They can cause a browning reac- also diminished when fed with dietary sor-
tion in foods through the action of polyphe- ghum tannins.29,30 Sorghum tannins have been
nol oxidase by darkening reactions ad- reported to cause leg abnormality in hens,
426
FIGURE 4. Examples of flavan-3-ols.
427
FIGURE 5. Some naturally occurring flavan-3,4-diols.
and delay in physical or sexual maturity, or feed intake and higher total protein intake
even death in hamsters.21 Dietary tannic acid than those fed on a low tannin-containing
caused nitrogen retention in chicks31 and diet, the groups on high-tannin diets showed
other test animals. Animals fed on tannin- a significant decrease in weight gain and
free diets had higher feed consumption and growth rate.36,37 Such a phenomenon has also
weight gains, compared with those fed on a been noticed with rats and swines.32,33,38–40
diet with endogenous tannin or tannin Rats could tolerate up to 5% tannins mixed
supplementation for an extended period of in a good ration.41 However, a much higher
time.27,32–35 Although animals fed on high content of tannins caused a marked growth
tannin-containing diets had a higher total depression.41 Increased quantities of insoluble
428
nitrogen were found in the digestive system tive tannins were usually with a larger mo-
of rats fed with high levels of tannins.42 lecular size. Polyphenols of low molecular
Mehansho et al.43 and Asquith et al.44 dem- weight are less reactive.54,55
onstrated that both hamsters and mice grew Tannins were reported to interfere with
relatively slowly when tannins were present the digestion and/or absorption of carbohy-
in their diet. Eggum and Christensen45 dis- drates from sorghum34 and in vitro amyloly-
covered that the addition of tannic acid to rat sis of sorghum starch.56 Zitko and Rosik57
diet decreased protein and amino acid di- reported that one tannin molecule could bind
gestibility and net protein utilization. The to two or more peptide groups, possibly
availability of amino acids was significantly through formation of crosslinks between
lowered in high tannin-containing diets com- protein chains. The degree of cross-linkage
pared with low tannin-containing diets.46,47 depends after the number and accessibility
Tannins have been shown to significantly of protein carbonyl groups, as well as the
depress the digestibility of dietary proteins relative concentration of the reactants.
in animals.48 Hagerman and Butler58 reported that under
Mehansho et al.49 showed that tannins optimal conditions sorghum tannin is ca-
bound to epithelial proteins causing precipi- pable of binding and precipitating at least 12
tation penetrated through the superficial cells times its own molecular weight of proteins.
and then caused liver damage. Tannins have High tannin sorghum grains contains more
been shown to inhibit virtually every diges- than enough tannins to bind to seed proteins
tive enzyme50 and reduce the bioavailability and profoundly affects the properties and
of iron and vitamin B12.51 Tannins are be- availability of these proteins. Barley, rye,
lieved to be responsible for fatal poisoning and common beans contain a low quantity of
of domestic animals fed on corns and other tannins and a higher level of protein; there-
high tannin-containing feeds. Toxic effects fore, the quality of seed proteins is less af-
have been attributed to consumption of ex- fected by tannins.59
cessive amounts of other high tannin-con- Four types of linkages are involved in
taining feed, including carob, certain sor- protein-tannin complexes: hydrogen-bond-
ghums, rapeseed meal, and grapeseed meals. ing,60 hydrophobic interaction,61 electrostatic
Human fatalities have occurred from con- attractions, and covalent bonding associated
sumption of high concentrations of tannic with oxidation.62 Tannins were reported to
acid in enemas or burn remedies.52 bind to proteins primarily through multiple
Tannins can interact with proteins, but hydrogen bonds formed between the phe-
their molecular size is important for such nolic hydroxyl groups of tannins and the
interactions. To be an effective crosslinking carboxyl groups of the peptide linkage of
agent, the tannin molecule must be small proteins.63–65 Hagerman and Butler 66 showed
enough to be able penetrate the interfibrillar that tannins have high affinities for proline-
region of protein fibers, but at the same time containing proteins.
be large enough to penetrate crosslinked Tannins, particularly the condensed types
protein chains at more than one site.53 A are reported to inhibit the enzymatic activi-
minimum of 350 D is required for tannins to ties of cellulase,67 pectinase,68 amylase,69 li-
effectively precipitate proteins. For con- pases,70 proteolytic enzymes,71 β-galactosi-
densed tannins, this would begin to occur dase,72 and those microbial enzymes involved
with the dimeric flavonoids. For hydrolyz- in fermentation of cereal grains.73 Inhibition
able tannins, a minimum of two gallic acid of enzymes by tannins is reported to be non-
precursor units or one ellagic acid would be competitive.72,73 The decreased enzymatic
the theoretical requirement. The more reac- activity may also come from the binding of
429
tannins with protein substrates, resulting in was not related to inhibition of food con-
formation of complexes resistant toward sumption or digestion. Instead, the major
hydrolysis.74 effect was on the efficiency with which the
Although tannins were shown to inhibit digested and absorbed nutrients were con-
most enzymes in vitro, there was little evi- verted into new body substance. This would
dence to indicate that such inhibition was be due to their direct inhibitory effect on a
significant in vivo. In the digestive tracts of key metabolic pathway or the indirect effect
higher animals membrane components pro- related to diversion of metabolism into
tect the digestive enzymes from dietary detoxification of polyphenols and/or their
tannins.21 Dietary tannins had little effect on degradation products. In either case, the site
the morphology of rat gut or mucein affected was not the intestine, but rather was
execretion.75,76 There was no direct evidence within the body where the absorbed compo-
to show that tannins interfere with nutrient nents exert the systemic effects. They fur-
uptake. It is generally agreed that the major ther suggested that low-molecular-weight
dietary effect of condensed tannins within polyphenol components associated with
the digestive tract was due to the formation tannins were more readily absorbed than were
of less-digestible complex with dietary pro- tannins themselves.87
teins, rather than the direct inhibition of the In brief summary, tannins are consid-
digestive enzymes.77 ered nutritionally undesirable. It is advisable
Tannins were reported to be deleterious not to consume tannin-containing foods in
to the alimentary canals of animals. Inges- large quantity. Exactly how large quantities
tion of high levels of tannins could cause of tannins can be ingested without causing
gastroenteritis and congestion of intestinal ill effects remain to be studied. The possible
wall in rats78 and hemorrhagic gastroenteri- influence of tannins or other components
tis in rabbits.79 Tannins extracted from faba associated with tannins in reducing the effi-
bean hull formed complexes with compo- ciency in converting the digested and ab-
nents of intestinal brush-border and impaired sorbed nutrients into new body substances
sugar transport in the intestine.80,81 requires further study.
Tannins are known to affect the utiliza-
tion of vitamins and minerals. Inclusion of
tannic acid in the diet resulted in a reduction III. TANNINS AS CARCINOGENS
of vitamin A content in rat liver.82 The ab-
sorption of vitamin A was impaired in the Polyphenols of tea have been reported to
presence of tannic acid. Tannins were also promote skin cancer in mice.88 Morton,89
found to interfere with the utilization of vi- based on results of epidemiological studies,
tamin B12.83 Tannins form insoluble com- also associated plant tannins with human
plexes with divalent iron and render them cancers. However, Salunkhe et al.90 suggested
less absorbable.84 Belavady85 found a marked that the conclusions of these studies were
reduction in iron absorption by human sub- based on results from inadequate experimen-
jects fed a sorghum containing 1500 ppm tal design and speculation. Stoltz91 reported
tannins. Motilva et al.86 also reported that that tannins were both mutagens and car-
faba bean tannins exhibited high iron-bind- cinogens. Tannins applied to burns or in-
ing capacities. jected subcutaneously were reported to cause
In a recent study on biochemical mecha- tumors in experimental animals.92,93 Because
nism of the antinutritional effects of tannins, tannic acid is hepatocarcinogenic to rat, it
Butler and Rogler87 demonstrated that the has been implicated as the etiology of hu-
major effect of dietary condensed tannins man liver cancer in certain geographic ar-
430
eas.92–94 Tannins and tannic acid have been People from the Caribbean use sorghum
listed as tentative carcinogens of Category I as a staple. They also heavily consume herbal
by the Occupational Safety and Health Ad- tea, such as mate. For the people of the
ministration (OSHA).95 Quercetin was iden- Caribbean islands, use of sorghum might
tified as a mutagen; it has been shown to be account in part for the cases of stomach and
carcinogenic to two strains of rats but not the other cancer seen there.50,107–110 Kapadia et
hamsters or mice.96 Dietary quercetin at 0.1% al.111 also expressed concerns about the safety
induced intestinal and bladder carcinoma in of herbal tea and its possible relationship
Norwegian rats.97 This compound also sig- with the incidence of esophageal cancer.
nificantly increased the occurrence of liver Kinlein et al.,112 in a case-control study in
tumors in Sprague-Dawley and Fisher 344 London, demonstrated a positive correlation
rats.98,99 Other tannin-related compounds, between tea consumption and the occurrence
rutin, kaempferol, and catechin, have also of stomach, lung, and kidney cancers. The
been suspected to cause cancers.99–102 increase in stomach and lung cancers might
Betel nuts containing 11 to 26% tannins be due, in part, to the effect of social class
are believed to be responsible for high levels and smoking. Morton113 claimed that exces-
of cheek and esophageal cancers in the Far sive consumption of bush-tea may be a caus-
East, where people chew these nuts after ative factor for the high incidence of esoph-
dinner.103 Ranadive et al.104 studied the car- ageal cancer in many populations. Kapadia
cinogenicity of betel quid ingredients: betel et al.114 investigated the effect of different
nut, betel leaf, lime, catechu, and tobacco in tannin solutions on the carcinogenic action
hamster check pouch, and concluded that of benzo[a]pyrene (B[a]P). The appearance
betel nut, particularly the tannin-containing of tumors was accelerated in mice treated
fraction, and its combination with lime and with either tea or an oak extract after a single
tobacco were potent carcinogens. Morton105 topical application of B[a]P. The time of
reported that certain tannin-rich beverage, tumor appearance in mice treated with gallic
masticalories, and folk remedies, including acid or tannic acid after B[a]P treatment was
guarna (Pallinia cupana HBK) from Brazil, similar to the group treated with B[a]P alone.
kola nut (Cola nitida Schott and Endl, and The overall incidence of tumors was the
C. acuminata Schott and Endl) from West same. Bogovski et al.115 also reported that
Africa, and betel nut (Areca catechu L) from topical application of black tea infusion after
Malaya, are now appearing in North Ameri- initiation treatment with B[a]P resulted in a
can sundry shops and grocery stores. Kapadia weak promotion of cancer. Ramanathan et
et al.106 found that animals injected with the al.116 reported that tannic acid at 5 to 5000
extract of betel nut all developed tumors. µM promoted B[a]P-induced skin carcino-
Panigrahi and Rao107 examined the geno- genesis in mice, but not at a concentration of
toxicity of betel nut and its tannins using >25 mM. It seems that chronic ingestion of
sister chromatid exchange (SCE) assay of a high amount of tannins in the diet may
mouse bone marrow cells. Betel nuts ex- increase the risk of some tumorigenic dis-
tracts induced a dose-related increase in SCE eases.
frequency after five daily doses at 12.5, 25, However, several studies have showed
or 50 µg/g. Significant increases in SCE that the two- to threefold increases of the risk
were also observed in animals dosed for 10 of esophageal cancer with the ingestion of
days with 25 or 50 µg/g extract. Mice dosed very hot tea was due to the hot temperature
with tannin at 200 µg/g for 10 days or 100 or rather than the tea itself.117–119
200 µg/g for 15 days showed significant Ghadirian120 studied the epidemiology
increases in SCE frequencies. of esophageal cancer in northern Iran and
431
found that 62% of the adult population in the the other molecules associated with tannins.
high-risk region drank the tea at a tempera- Nevertheless, tannins may act as a co-car-
ture of over 65°C as opposed to 19% in the cinogen or promoter in inducing skin car-
low-risk region. Consumption of bread con- cinogenesis in the presence of other carcino-
taminated with silica fiber, and ingestion of gen. This possibility warrants further
opium and opium dross in combination with research.
the the long-lasting and daily thermal irrita-
tion of esophagus with very hot tea may play
important roles in inducing esophageal can- IV. TANNINS AS
cer. Singleton121 claimed that the carcinoge- ANTICARCINOGENS
nicity of tannins might be due to irritation
and cellular damage instead of DNA mu- An inverse correlation exists between
tagenesis. Nagabhushan et al.122 tested the individuals who consume a diet rich in fruits
mutagenicity of tannin fractions of commer- and vegetables and their risk in developing
cial tea and tannic acid among others and cancers.126,127
found that tannic acid from tea was not Stokes,128 in an investigation covering
mutagenic to Salmonella typhimurium tester 20 countries, showed a significant negative
strains TA98, TA100, TA1535, and TA1538 association between tea consumption and
with or without metabolic activation (rat-S9 stomach cancer incidences in individuals of
mix). These fractions did not increase tumor both sexes. Japanese individuals consuming
incidence in Swiss mice given by gavage green tea more frequently or in large quan-
feeding. A recent study by Onodera et al.123 tities tended to have a lower risk of gastric
using F344 rats of both sexes showed that cancer.129 The cancer death rate, especially
tannic acid given ad libitum at 0.25 and 0.5% from stomach cancer, in tea production area
in distilled water for up to 2 years did not was lower than the non-production area.130
significantly increase the incidence of any The town inhabitants who tended to drink
tumor. Thus, tannic acid has no carcinogenic green tea more frequently had lower inci-
potential in F344 rats or modifying effects dences of stomach cancer than those living
on development of spontaneous tumors. Tan- in other areas who did not drink as much tea.
nic acid was found not to be mutagenic or The inhibitory effect of green tea on
clastogenic to germ cells of male Droso- cancer formation has been well studied.
phila melanogaster.124 Conney et al.131 demonstrated that topical
Despite these experimental facts, Battista application of green tea polyphenol fraction
et al.125 pointed out that natural tannins were inhibited 12–0-tetradecanoylphorbol-13-ac-
regarded as possible etiological agents for etate (TPA)-induced tumor promotion in
nasal cancer in shoe-making and shoe-re- mouse skin. Oral administration of green tea
pairing workers in Italy. inhibited ultraviolet light-induced tumorigen-
The use of population correlations might esis in mouse skin. Oral administration of
not reflect a true cause-effect relationship. green tea to papilloma-bearing mice inhib-
Usually, environmental influence, occupa- ited tumor growth, and in some incidence
tion, heavy smoking, high consumption of caused a decrease in tumor size.131 Wang et
alcoholic beverages, poor nutrition, and use al.132 demonstrated that oral administration
of emetics better correlate with the incidence of green tea infusion as the sole source of
of cancer than does the diet. It seems that the drinking water to A/J mice markedly inhib-
correlation between betel nuts or herbal tea ited N-nitrosodiethylamine (NDEA)-induced
with certain types of cancer is not necessar- tumorigenesis. Oral administration of
ily related to tannins themselves but rather decaffeinated green tea and black tea ex-
432
tracts (0.6%) also inhibited 4-(methylnitro- duodenum of mice.144 Fujiki et al.145 also
samine)-1-(3-pyridyl)-1-butanone (NNK)- demonstrated that EGCG inhibited duo-
induced lung tumorigenesis in A/J mice.132 denal carcinogenesis induced by MNNG.
Yamane et al.133 showed that oral adminis- Yoshizawa et al.146 showed that EGCG
tration of 0.01 or 0.1% green tea polyphe- inhibited tumor promotion in two-stage
nols in drinking water inhibited azoxy- carcinogenesis of mouse skin using DMBA
methanol-induced colonic tumor in rats. as the initiator and teleocidin as the pro-
Huang and Ferrao134 reviewed the effect of moter. EGCG and penta-o-galloyl-β-D-glu-
green tea and found that different types of cose (5-GG) strongly inhibited the specific
tumors, including esophageal, forestomach, TPA binding to phorbol ester receptors on
duodenum, small intestine, colon, lung, liver, mouse skin cells.137 Recent work of Shi et
mammary gland, pancreas, and skin of dif- al.147 demonstrated that, among decaffeinated
ferent animals were affected. green tea and black extracts and their frac-
The polyphenolic extracts of green tea, tions at concentration up to 0.4 mg/ml, EGCG
when applied to mouse skin, inhibited the was the most potent inhibitor to both NNK
tumorigenicity initiated by polycyclic aro- oxidation and DNA methylation. EGCG also
matic hydrocarbons such as B[a]P, 7,12- inhibited the catalytic activities of several
dimethylbenz[a]anthrance and N-methyl-N- P450 enzymes.
nitrosourea (MNU) and then promoted by Das et al.148 also showed that tannic acid
TPA, teleocidin, or okadaic acid.135–138 protected against the two-stage tumor proto-
Oral administration of the phenolic ex- col in Sencer mice using DMBA, B[a]P, and
tracts of green tea also inhibited mice skin MNU as the initiating agents followed by
tumor induced by UV light.139,140 Recently, two weekly applications of the promoter,
Wang et al.141 demonstrated that water ex- TPA. Tannic acid was found to be an effec-
tracts of black tea, green tea, decaffeinated tive inhibitor of tumor formation in reducing
black tea, and decaffeinated green tea were cumulative numbers of tumors per mouse
inhibitory to U.V.-induced skin carcinogen- and percentage of mice with tumors. Similar
esis in 7,12-dimethylbenz[a]anthracene results were also obtained by Athar et al.,149
(DMBA) initiated SKH-1 mice. The effec- who demonstrated that mice fed with tannic
tiveness of black tea was comparable to green acid-supplemented diet had a significantly
tea. Khan et al.142 demonstrated that tannic lower incidence of forestomach and pulmo-
acid and green tea polyphenols (GTP) af- nary tumors compared with animals fed a
forded significant protection against skin tu- control diet with B[a]P. They also showed
mor induced by (+)-7β,8α-dihydroxy- that animals receiving tannic acid-contain-
9α,10α−epoxy-7,8,9,10-tetrahydrobenzo[a] ing diet had diminished aryl hydrocarbon
pyrene (BPDE-2) in Sencar mice. Querce- hydroxylase and 7-ethoxyresorufin-o-
tin, on the other hand, showed only moder- deethylase activities in formstomach and
ate protection. lung. Elevated activities of glutathione-S-
Chung et al.143 showed that green tea transferase and NAD(P)H: quinone reduc-
could inhibit NNK-induced lung tumors in tase were observed in these tissues.149
mice, and the inhibitory effect appeared to Carr150 reported that rutin protected cer-
be due primarily to its major polyphenol, tain types of tumor, although Yu et al.151
epigallocatechin gallate (EGCG). Oral feed- showed that rutin in wine was a mutagen
ing of EGCG in drinking water during the following metabolic activation by liver and
postinitiation stage of carcinogenesis inhib- colonic enzymes. Quercetin has been found
ited N-methyl-N-niro-N′-nitroso-guanidine to be a potent anticarcinogen against
(MNNG)-induced tumor formation in the cancers of skin, colon, and mammary in
433
rodents.152–154 This compound may also in- drogen peroxide, benzoyl peroxide, anthra-
hibit human cancers.153,155 Ohshima and lin, chrysarobin, and n-dodecane.171 The
Bartsch156 demonstrated that chlorogenic and antioxidative and anti-tumor-promotion ac-
gallic acid inhibited nitrozation and thus the tivities of these hydrolyzable tannins were
formation of carcinogenic nitrosamine. Like- also examined. A single application of TPA
wise, gallic acid, caffeic acid, and chloro- gradually increased the hydroperoxide-
genic acid also reduced the formation of producing activity of the epidermis. Pre-
some mutagens.126 Ellagic acid has been re- treatment with tannic acid and ellagic acid
ported to significantly inhibit cancer forma- strongly inhibited, in dose-dependent man-
tion of colon, esophageal, liver, lung, tongue, ners, this hydroperoxide response to TPA.
and skin in rats and mice in both in vitro and On equal dose basis, ellagic acid is an anti-
in vivo investigations.157–166 Ellagic acid has oxidant at least 10 times more potent than
also been demonstrated to be a possible tannic acid and propyl gallate, which are
chemopreventive agent for human carcino- equally effective against TPA-induced hy-
genesis.166–168 Ellagic acid was reported to droperoxide production. For instance, as little
inactivate benzo[a]pyrene-7,8-diol-9,10- as 0.5 µmol of ellagic acid reduced the
epoxide.167,169 Cozz et al.170 pointed out that TPA-stimulated level of hydroperoxide by
ellagic acid might exert its anticarcinogenic 94%, while 10 µmol of tannic acid was
effects by: (1) inhibiting the metabolism of needed to provide the same inhibitory ef-
procarcinogen; (2) binding with DNA, mak- fects.172 Topical application of catechin,
ing methylation of O6- or N7-guanine less epicatechin, and semisynthetic flavonoids,
possible; and (3) scavenging adduct forma- catechin dialkyl ketals, or epicatechin-4-
tion with ultimate carcinogens. They showed alkylsulfides inhibited TPA-induced ODC
that ellagic acid acts against damage induced activity. Epicatechin-4-alkylsulfides and
by mitomycin-C and hydrogen peroxide in catechin dialkyl ketals also inhibited hy-
cultivated Chinese hamster ovary cells.170 droperoxide production and the sequential
Ellagic acid was proven to have a dual mecha- stimulation of protein and DNA synthesis
nism of action, either as a scavenger of oxy- linked to TPA promotion.173 Kuo et al.174
gen species produced by H2O2 treatment, or investigated the anti-promotion effects of
a protector of the DNA double helix from tannic acid on mouse skin carcinogenesis.
alkylating agent injury.170 They found that tannic acid effectively
Gali et al.171 reported that topic applica- blocked TPA-evoked phosphorylation of the
tions of tannic acid inhibited, in a dose-de- membrane-bound protein kinase C moiety
pendent manner, TPA-induced ornithine de- and its 80-kDa substrate in a dose-depen-
carboxylase (ODC) activity linking to skin dent manner. They suggested that the anti-
tumor promotion in mouse epidermis. Gallic tumor-promotion effect of tannic acid was
acid, ellagic acid, gallic acid methyl ester, not mediated by its competing for the bind-
gallic acid lauryl ester, and n-propyl gallate ing site with phorbol ester or interrupting
inhibit ODC response to TPA to a lesser the protein kinase C translocation, but rather
degree than tannic acid. Ellagic acid is by effectively blocking phosphorylation by
the least effective inhibitor tested. Tannic membrane-bound protein kinase C, possi-
acid also inhibits ODC activities induced bly through alteration of the biophysical
by several different tumor promoters such properties of the membrane environment.174
as 12-deoxyphorbol-13-tetradecanoate, Recent work by Gensler et al.175 demon-
mezerein, 12-oretinoylphorbol-13-acetate, strated that topical application of tannic acid
phorbol-12,13-didecanoate, phorbol-12,13- inhibited cutaneous carcinogenesis induced
diben-zoate, 1,2-dioctanoyl-sn-glycerol, (–)- by UV irradiation in BALB/cAnNTacfBR
indolactam V, (–)-7-octylindolactam V, hy- mice.
434
Miyamoto et al.176 demonstrated that Huang et al.180 showed that tannic acid in-
several oligomer of hydrolyzable tannins, hibited the mutagenic activity of (+)-7β,8α-
including agrimoniin, oenothein B, and dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahy-
coriariin A, had antitumor activities against dro-benzo[a]pyrene (B[a]P-7,8-diol-9,10-
sarcoma (Table 1). Agrimoniin induced cy- epoxide-2), an ultimate mutagen and car-
totoxic adherent peritoneal exidate cells cinogen of benzo[a]pyrene (B[a]P) using Sal-
(PEC) and natural killer cell activity.177,178 monella typhimurium TA100. The antimu-
Oenothein B, a macrocyclic ellagitannin from tagenic activity of tannic acid was a result of
Oenothera erythrosepala Bordes, induced its interaction with B[a]P-7,8-diol-9,10-
cytostatic macrophages to release interleukin epoxide-2. Tannic acid was a highly potent
I (IL-I)-like activity and IL-Ib. It is sug- inhibitor of the mutagenic bay-region diol-
gested that oenothein B exerts its anti- epoxides of benzo[a]pyrene, dibenzo
tumor effect through potentiation of the host [a,h]pyrene, and dibenzo[a,i]pyrene. Sim-
immune defense via activation of macroph- ilarily, tannic acid at higher concentrations
ages.179 inhibited the mutagenicities of the less reac-
tive benzo[a]pyrene 4,5-oxide and the bay-
region diol-epoxides of benzo[a]anthracene,
V. TANNINS AS ANTIMUTAGENS chrysene, and benzo[c]phenanthrene. 180
Gichner et al.181 demonstrated that tannic
The antimutagenic activity of different and gallic acid inhibited the mutagenicity of
component of tannins were also reported. MNU and MNNG in S. typhimurium TA100.
TABLE 1
Tannins Showing Anticarcinogenic Activity
Compound Type of tumors Ref.
Chlorogenic acid 166

Ellagic acid Colon, esophageal, 157, 159, 160, 161, 162, 163,
lung, tongue, and skin 164, 165, 167, 169, 170
(rodent)
Epigallocatechin- Duodenum 144, 145, 146
3-gallate (EGCG) Lung (mice) 143
Green tea polyphenols Skin (mice) 131, 135, 136, 137, 138, 139,
140, 142, 193
Colon 133
Green tea Papilloma (mice) 131
Esophageal, colon, 134
duodenum, lung,
forstomach, small
intestine, mammary
glands, and pancreas
Green tea infusion Lung (mice) 132
Quercetin Skin, colon and 152, 153, 154
mammary (rodents)
Skin 155
Rutin Colon (mice) 150, 152
Tannic acid Skin (mice) 148, 171, 172, 173, 174
Forestomach and 149
pulmonary
Tea consumption Gastric 128, 129, 130
435
The antimutagenic effects of these acids were hibited the mutagenicity of B[a]P (2.5 µg/
largely resulting from interactions between plate) in S. typhimurium TA98 with S9 mix.
MNU or MNNG with these tannins outside EGCG was shown to be a potent antimutagen
the bacterial cells. Wang et al.182 also showed against direct-acting mutagens.185 The in vivo
that the water extracts of green tea (WEGT) antimutagenic effects of tannic acid was also
and their major constituents, green tea demonstrated in mice by Sasaki et al.186 Tan-
polyphenols (GTP) were inhibitory to re- nic acid was given orally to pregnant female
verse mutation induced by B[a]P, aflatoxin C57BL/10 mice 6 h before intraperitoneal
B1(AFB1), 2-aminofluorene, and methanol injection of ethyl nitrosourea (ENU) on the
extracts of coal tar pitch in S. typhimurium 10th day of pregnancy. The frequency of
TA100 and/or TA98 in the presence of rat pups with recessive color spots induced by
liver S9 mix. GTP also inhibited forward ENU was significantly decreased by treat-
mutation in V79 cells treated with AFB1 and ment with tannic acid.186 Tannins showing
B[a]P and decreased the frequency of SCE antimutagenic activity are summarized in
and chromosomal aberrations in V79 cells Table 2.
treated with AFB1. Vance and Teel183 also The anticarcinogenic and antimutagenic
demonstrated that tannic acid inhibited rat potentials of tannins may be related to their
liver S9-mediated mutagenesis of B[a]P in antioxidative property in protecting cellular
S. typhimurium by 32 to 77% at 5 to 50 µg components from oxidative damages, includ-
B[a]P/plates. Tannic acid at 40 µM inhibited ing lipid peroxidation, DNA single-strand
B[a]P metabolites binding to calf thymus breakage, and formation of 8-hydroxy-
DNA by 40%, and B[a]P-7,8-dihydrodiol- deoxyguanosine. For example, quercetin had
9,10-epoxide (BPDE): deoxyguanosine ad- been demonstrated to inhibit the generation
duct formation in calf thymus DNA by 12 to of superoxide anions by neutrophils.187 Fla-
54% at 10 to 40 µM.183 Horikawa et al.184 vonoids were able to inhibit the release of
also demonstrated that epigallocatechin, myeloperoxidase or its activity, which in turn
EGCG, epicatechin gallate, and tannic acid resulted in reduced production of active oxy-
isolated from extracts of Chinese medicinal gen species.188 Quercetin and rutin had been
herbs Prunella spica, Rheum palmatum, demonstrated to scavenge superoxide an-
Polygonum multiflorum, Agrimonia pilosa, ions.189 Geraniin, 5-GG, EGCG, and several
Ephedea sinica, and Teitoutou strongly in- polyphenols had been reported to inhibit lipid
TABLE 2
Tannins Showing Antimutagenic Activity
Compound Mutagen Ref.
Epigallocatechin, B[a]P 184

Epigallocatechin-gallate,
Epicatechin gallate
Gallic acid MNU, MNNG 181
Green tea polyphenols B[a]P, aflatoxin B1 and 182
2-aminofluorene
Tannic acid B[a]P-7,8-diol-9,10-epoxide, 180
B[a]P-4,5-oxide,
B[a]anthracene epoxide,
B[a]phenathrene
MNNG 181
B[a]P 183, 184
ENU 186
436
peroxidation in lense.190 The generation of growth of Colletotrichum graminicola. The
superoxide radicals was also inhibited by growth of other fungi such as Coniophora
tannins and other related compounds.191,192 olivacea, Gloeophyllum trabeum, Trametes
Laskin et al.193 recently showed that the in- hirsuta, and Trichoderma viride were all re-
hibitory effect of tea polyphenol fraction on ported to be inhibited by different prepara-
tumor promotion may be related to its ability tions of tannins.202–205 Harris and Burns206
in reducing free radical formation in mouse also reported that sorghum grain inhibited
epidermis. the growth of various preharvested seed
Contradictory reports were reported con- molds; they attributed the inhibition to the
cerning the anti-carcinogenicity of tannins. effect of tannins. Filamentous fungi suscep-
Tannins seemed to exert anticarcinogenic tible to the inhibitory/toxic effects of tannins
activities at a certain concentration range are summarized in Table 3.
and tumor-promoting activities while at con- Yeasts are also sensitive to tannins
centrations beyond that range. Unfortunately, (Table 4). Jacob and Pignal207 demonstrated
experimental results covering a wide range that tannic acid, chestnut tannin, and quebra-
of concentrations are rare and incomplete. cho tannin inhibited the growth of various
An animal model should be developed for yeast species. Some species were inhibited
further research in order to resolve such a by tannins at 25 g/l, while others were inhib-
dilemma. ited at a much higher concentration of tannin
(125 g/l). Yeasts were generally more sensi-
tive to chestnut tannin than to quebracho
VI. TANNINS AS ANTIMICROBIAL tannin.207 Mullins and Nesmith208 also re-
AGENTS ported that Saccharyomyces cerevisiae was
inhibited by sorghum grain, presumably by
The antimicrobial property of tannins has its tannins.
been well documented. Haars et al.194 dem- Tannins have been reported to be bacte-
onstrated that tannins of unknown origin riostatic and/or bactericidal for Staphylococ-
inhibited the growth of filamentous fungi cus aureus, Streptococcus pnumonia, Bacil-
Fomes annosus with a minimum inhibitory lus anthracis, Shigella dysenteriae, and
concentration (MIC) greater than 0.5 g/l. Salmonella senftenberg. 209,210 Bacillus
Wehmer195 showed that tannic acid at 10 to subtilis, B. stearothermophilus, Clostridium
20 g/l inhibited the growth of Merulius botulinum, and Desufomaculum nigrificans
lacrymans and Penicillium species. Brownlee were inhibited by flavonoids and purified
et al. 196 reported that germination of theaflavins.211 The growth of Desulfovibrio
Crinipellis perniciosa basidiospores was species was also reported to be inhibited by
suppressed by condensed tannins (procy- tannic acid.212 Waage et al.213 demonstrated
anidin) from cocoa (Theobroma cacao) ex- that Machaerium floribundum and cotton
tract at 0.25 g/l. Jersch et al.197 also showed condensed tannins were inhibitory to the
that condensed tannins from strawberry in- growth of Enterobacter cloacae and
hibited the growth of Botrytis cinerea. The Pseudomonas maltophila. Important soil
growth of wood-decaying Coriolus versi- bacteria such as Nitrobacter species and
color and Poria monticola was inhibited by Nitrosomonas species were inhibited by
ellagitannin from white oak,198 and Aspergil- chestnut tannin, hydrolyzable tannins, and
lus niger and Chaetomium cupreum inhib- tannic acid.214 Baldwin et al.215 also reported
ited by myrobalan tannin and wattle tan- that soil bacteria were inhibited by chestnut
nin.199,200 Nicholson et al.201 found that tannin. Nishizawa et al.216 found that Pro-
condensed tannin was inhibitory to the teus vulgare and Staphylococcus aureus were
437
TABLE 3
Filamentous Fungi Susceptible to the Toxic Effect of
Tannins
Fungi species Tannin Ref.
Botrytis cinerea Condensed tannins 197

(strawberry)
Colletotrichum graminicola Condensed tannin 201
Coniophora olivacea Tannin (Eucalypt) 202
Coriolus versicolor Ellagitannin (white oak) 198
Crinipellis perniciosa Tannins (procyanidin) 196
(cocoa extract)
Fomes annosus Tannins 194
Gloeophyllum trabeum Ellagitannin (iron wood, 203
white oak)
Merulius lacrymans Tannic acid 195
Penicillium sp. Tannic acid 195
Poria monticola Ellagitannin (white oak) 198
Trametes hirsuta Tannic acid 204
Trichoderma viride Condensed tannin 205
TABLE 4
Yeast Susceptible to the Toxic Effect of Tannins
Yeast species Tannin Ref.
Candida albicans Water and ethanol extracts 226

of Bridelia ferruginea
Corilagin, punicalagin, 228
1,3,6-tri-o-galloyl-β-D-
glucopyranose, chebulagic
acid, 1,2,3,4,6-penta-o-
galloyl-β-D-glucopyranose
Saccharomyces cerevisiae Sorghum grain 208
Various yeasts Tannic acid, 207
tannin (chestnut, quebracho)
inhibited by 2,3,4-tetrakis(3,4,5-trihy- to be inhibited by the leaf extracts of Aesculus

droxybenzoyl)-α-D-glucosylpyranose and hippocastanum and Acer platanoides, which
ellagitannins, the purified hydrolyzable contain considerable amounts of polyphe-
tannins from the roots of Canadian water nols, tannic acids, coumarin, and flavo-
lily Nuphar variegatum. Tannic acid was noglucids.219 Field and Lathinga220 reported
also inhibitory to Photobacterium phos- that the growth of methanogenic bacteria
phoreum.217 was affected by tannins.
Muthukumar and Mahadevan218 demon- Many disease-associated bacteria were
strated that Pseudomonas solanaceacrum and affected by tannins. Cariogenic bacteria such
Polyangium specis were suppressed by my- as Streptococcus mutan and S. sobrinus were
robalan tannin and wattle tannin. Slimy bac- inhibited by pentagalloylglucose (PGG),
teria Sporocytophaga species was reported purified oligomeric condensed tannins,
438
flavanols, and flavanols gallate.221–223 Wu- monocytogenes 1A1, Prot. vulgaris, Pseud.
Yuan et al.224 reported that gallotannin in- fluorescens, Salmonella enteritidis, S. para-
hibited the growth, synthesis of water-in- typhi, Shigella flexneri, Staphyl. aureus,
soluble glucan, and aggregation of mutans Strept. faecalis, Strept. pyogenes, and
streptococci. The growth of various diar- Yersinia enterocolitica. They further discov-
rhea-causing pathogens was inhibited by tea ered that the inhibitory effect of these com-
extracts. 225 Hospital strains of Staphyl. pounds was associated with the ester linkage
aureus, Staphyl. epidermis, Candida al- between gallic acid and polyols. Similar in-
bicans, Escherichia coli, Strept. lactis, Prot. hibitory effects were also found with aquatic
vulgaris, Prot. mirabilis, Strept. pyogenes, bacteria including Aero. hydrophila, Aero.
and Klebsiella spp. were reported to be in- sobria, Edwardsiella ictaluri, Edward. tarda,
hibited by ethanol extracts of Boridelia Pseud. fluorescens, and E. coli.231 Chung et
ferruginea at 5 mg/ml. Phytochemical analy- al.232 also demonstrated that tannic acid, pro-
sis of this plant extract showed the presence pyl gallate, and gallic acid inhibited the
of tannins and phenols.226 Hara et al.227 re- growth and pigment synthesis of Nostoc. sp.
ported that foodborne pathogens such as strain MAC and Agmenellum quadrup-
Vibrio parahaemolyticus, V. fluvialis, liacatum strain PR-6, a cyanobacterium com-
V. metschnikovii, Staphyl. aureus, Clost. monly found in aquatic environment. The
perfringens, Bacillus cereus, Plesiomonas common catfish pathogen Flexibacter
shigelloides, and Aeromonas sobria were columnaris is also inhibited by tannic acid
inhibited by flavanols and purified theafla- (Chung et al., unpublished results). Bacteria
vins. Antimicrobial activity of tannins in- susceptible to the toxic effect of tannins are
cluding corilagin, punicalagin, 1,3,6-tri-o- summarized in Table 5.
galloyl-β-D-glucopyranose, chebulagic acid, Tannins have also been reported to inac-
and 1,2,3,4,6-penta-o-galloyl-β-D -gluco- tivate virulence of viruses such as tobacco
pyranose from Terminalia citrina Roxb mosaic virus233–235 or Herpes Simplex vi-
(Combretaceae), commonly found in Thai- ruses236 (Table 6). Green237 demonstrated that
land as traditional medicine for diarrhea and tannic acid inhibited the multiplication of
some skin infections, were also reported.228 influenza virus. Carlson and Frisch238 re-
Susceptible microorganisms tested included ported inactivation of influenza virus by tan-
Staphyl. aureus, E. coli, Pseud. aeruginosa, nic acid and related compounds. Inactiva-
K. pneumoniae, and Candida albicans. tion of coxsackievirus, echovirus, reoviruses,
Aguwa and Lawal229 studied the pharmaco- herpes viruses, and polioviruses by tannins
logical effects of the leaf extract of has also been reported.239,240 Mizuno et al.241
Galliandra portoricensis, which was used as recently demonstrated that tannic acid sul-
a herbal drug for gastrointestinal disorders fate, rutin sulfate, ellagic sulfate, (–)-
in southern Nigeria. They found that the epicatechin sulfate, and (–)-epigallocatechin-
active principles of the leaf extracts con- 3-gallate sulfate inhibited infections of human
tained saponins and/or tannins and had anti- T-cell lymphotrophic virus type-1-carrying
microbial effect against E. coli, Staphyl. MT-4 cells by human immunodificiency vi-
aureus, and Strept. faecalis.229 rus (HIV). Tannic acid sulfate at 6 µg/ml
Chung et al.230 demonstrated that tannic completely inhibited the cytopathic effect of
acid and propyl gallate but not gallic acid HIV and HIV-specific antigen expression in
were inhibitory to the growth of foodborne MT-4 cells. This compound at 5 µg/ml also
bacteria, including Alcaligenes faecalis, inhibited giant cell formation in HIV-infected
Enterobacter aerogenes, E. coli, K. pneu- and HIV-uninfected co-culture cells. 241
moniae, Listeria monocytogenes Scotts A, L. Nishizawa et al.242 also demonstrated that
439
TABLE 5
Bacteria Susceptible to the Toxic Effect of Tannins
Bacterial species Tannin Ref.
Aeromonas hydrophila Tannic acid, propyl gallate 231

Aeromonas sobria Flavanols, theaflavins 227
Tannic acid, propyl gallate 231
Agmenellum
quadruplicatum PR-6 Tannic acid, propyl gallate 232
Alcaligenes faecalis Tannic acid, propyl gallate 230
Bacillus cereus Flavanols, theaflavins 227
Bacillus anthracis Tannins 210
Bacillus subtilis Flavanols, theaflavins 211
B. stearothermophilus
Clostridium botulinum
Clostridium perfringens Flavanols, theaflavins 227
Desulfomaculum Flavanols, theaflavins 211
nigrificans
Desulfovibrio sp. Tannic acid 212
Edwardsiella ictaluri Tannic acid, propyl gallate 231
E. tarta
Enterobacter aerogenes Tannic acid, propyl gallate 230
Enterobacter cloacae Procyanidin, condensed 213
tannin (cotton)
Escherichia coli Leaf extract of 229
Galliandra portoricensis
Ethanol extracts of 226
Boridelia ferruginea
1,3,6-tri-o-galloyl-β-
Klebsiella pneumoniae Tannic acid, propyl gallate 230
acid,1,2,3,4,6-penta-o-
Klebsiella sp. Ethanol extracts of 226
Listeria monocytogenes Tannic acid, propyl gallate 230
Nitrobacter sp. Tannins (chestnut), 214
Nirrosomnas sp. hydrolyzable tannin,
tannic acid
Nostoc sp. Tannic acid, propyl gallate 232
Photobacterium Tannic acid 217
phosphoreum
Plesiomonas shigelloides Flavanols, theaflavins 227
Polyangium sp. Tannins (myrobalan 218
and wattle)
Proteus mirabilis Ethanol extracts of 226
440
TABLE 5 (continued)
Proteus vulgare 2,3,4-tetrakis-(3,4,5– 216

trihydroxybenzoyl)-α-D-
glucosylpyranose,
ellagitannin
Proteus vulgaris Tannic acid, propyl gallate 230
Pseudomonas aeruginosa Corilagin, punicalagin, 228
Pseudomonas fluorescens Tannic acid, propyl gallate 230, 231
Pseudomonas maltophila Procyanidin, condensed 213
tannin (cotton)
Pseudomonas Tannin (myrobalan and 218
solanaceacrum wattle)
Salmonella enteritidis Tannic acid, propyl gallate 230
Salmonella paratyphi Tannic acid, propyl gallate 230
Salmonella senftenberg Tannin (pecan) 209
Shigella dysentereae Tannins 210
Shigella flexneri Tannic acid, propyl gallate 230
Sporocytophaga sp. Leaf extract of 219
Aesculus hippocastanum
and Acer platanoides
Staphylococcus aureus Tannins 210
Leaf extract of 229
Flavanols, theaflavans 227
2,3,4-tetrakis-
(3,4,5-trihydroxybenzoyl)- 216
α-D-glucosylpyranose,
ellagitannin
corilagin, punicalagin,
1,3,6-tri-o-galloyl-β-D- 228
Staphylococcus epidermis Ethanol extracts of 226
Streptococcus faecalis Leaf extract of 229
Streptococcus lactis Ethanol extracts of 226
Streptococcus mutans PGG, condensed tannin, 221, 222, 223
flavanols gallate
Gallotannins 224
441
TABLE 5 (continued)
Streptococcus pneumonia Tannins 210

Streptococcus pyogenes Tannic acid, propyl gallate 230
Streptococcus sobrinus PGG, condensed tannin, 221, 222, 223
Flavanols gallate
gallotannins 224
Vibrio fluvialis Flavanols, theaflavins 227
V. metschnikovii
V. parahaemolyticus
Yersinia enterocoliticca Tannic acid, propyl gallate 230
TABLE 6
Viruses Susceptible to the Toxic Effect of Tannins
Name of viruses Tannin Ref.
Coxsackie virus, Tannins (fruits) 239

Echo virus
Herpes viruses Tannins (fruits) 239
Tannins 236
HIV viruses Tetragalloylquinic acids 242
Punicalin 243
Anthroquinones 244
Flavonoids 245
Tannic acid sulfate, 241
rutin sulfate, ellagic sulfate,
epicatechin sulfate,
(–)-epigallocatechin-3-gallate
sulfate
Epigallocatechin, epicatechin, 246
epicatechin-3-o-gallate,
epigallocatechin-3-o-gallate
Influanza virus Tannic acid 237, 238
Newcastle disease, Extracts of Melissa officinalis 240
vaccinia, Semliki
Forest, and
West Nile viruses
Polio virus, Tannins (fruits) 239
Reovirus
Tobacco mosaic Tannins (strawberry) 233, 234, 235
virus
tetragalloylquinic acids inhibited reverse tran- 50% inhibition dose (ID50) of 8 µM.243 Anti-
scriptase (RT) activity of HIV at the concen- viral activities of anthroquinones244 and fla-
tration of 30 µM. Another tannin compo- vonoids245 on RT had also been reported.
nent, punicalin, inhibited RT of HIV with a Chang et al.246 recently demonstrated that
442
epigallocatechin, epicatechin-3-0-gallate, and Most tannin molecules have more than two
epigallocatechin-3-0-gallate isolated from o-diphenol groups and are thus capable of
Chinese green tea Camella sinensis were forming chelates with many metal ions such
inhibitory to HIV-RT, and the IC50 were as ferric or cupric ion.256 The multicatecholate
7.80, 0.32, and 0.68 µM, respectively (Table nature of tannins that allows reticulation is
6). the origin of the formation of metal-tannin
precipitate.257,258 Therefore, tannins will re-
duce the availability of essential metal ions
VII. EFFECTS OF TANNINS ON for microorganisms, just as tannins reduce
MICROBIAL ENZYME ACTIVITIES the absorption of nutrients in rats given tan-
nin-rich beverages like tea or cocoa.259
Scalbert212 summarized the antimicrobial Tannins have been shown to be good inhibi-
mechanisms of tannins as follows. (A) The tors of fungal metalloenzymes such as per-
astringent characters of tannin may induce oxidase and laccase, compared with other
complexation with enzymes or substrates. enzymes such as cellulase, pectinase,
Many microbial enzymes in raw culture fil- xylanase, or protease.250
trates or in purified forms were inhibited There are probably multimechanisms
when mixed with tannins: cellulase,247–249 involved in tannin toxicity, depending on
pectinase,250,251 xylanase,250 peroxidase,247,250 the individual microorganism. Research us-
laccase,250 and glycosyl transferase.218,219 This ing purified tannins rather than crude ex-
is evidenced from the reduced inhibitory tracts may lead to illustrate exactly how
effect of tannin following addition of a ligand tannins inhibit the growth of different mi-
such as serum albumin that competes with croorganisms.
microbial enzymes.196 If tannin toxicity is
due to their astringent characters, one would
expect that higher toxicity would correlate VIII. OTHER BIOLOGICAL EFFECTS
with higher molecular weight of tannin com- AND APPLICATIONS OF TANNINS
pounds. For example, the toxicities of (–)-
epicatechin gallate and (–)-epigallocatechin Tannins also possess other biological
gallate toward Clost. botulinum would be activities (Table 7). Ellagic acid was reported
greater than the toxicities of their ungallated to accelerate blood clioting260 and used to
counterparts (–)-epicatechin and (–)- control hemorrhage in animals261,262 and hu-
epigallocatechin.252 mans.263 Ellagic acid was also reported to
However, this is not always the case. In reduce blood pressure in experimental ani-
some instances, the toxicity of tannin is not mals, possibly through the antagonistic ef-
higher than that of catechin, although the fect on histamine liberators.264
latter has a very poor affinity for pro- Tannic acid is a hepatotoxin; it produces
tein.252–254 (B) Tannin toxicity may be re- hepatic necrosis in humans and grazing ani-
lated to their action on the membranes of the mals.265–270 Reddy et al.271 demonstrated that
microorganisms.212 Inhibition of the electron a single subcutaneous injection of tannic acid
transport system was observed with Photo- at 700 mg/kg body weight caused a signifi-
bacterium phosphoreum following treatment cant breakdown of polyribosome in mouse
with tannic acid.214 (C) Complexation of liver and inhibited the incorporation of amino
metal ions by tannins could be the third pos- acids into hepatic cellular proteins. Rao et
sible mechanism responsible for tannin tox- al.272 also demonstrated that tannic acid, when
icity. Antimicrobial activity through iron injected into rat hepatocytes, caused nucle-
depletion is well documented.255 Metal deple- olar alterations in homotopic liver. Hamster
tion may affect the activity of metalloenymes. and rat hepatocytes xenotransplanted into
443
TABLE 7
Miscellanous Physiological Effects of Tannins
Tannins Effect Ref.
Agrimoniin Immune response 178

Apigenin Venom poisoning 273
Ellagic acid Blood clotting 260
Hemorrhage 261, 262, 263
Blood pressure 264
Kaempferol Venom poisoning 273
Luteolin Venom poisoning 273
Tannic acid Hepatotoxicity 265, 266, 267, 268,
269, 270, 271, 272,
274, 275, 276
Lipid metabolism 274, 275, 276
Venom poisoning 273
Immune response 280
Hemagglutination test 283, 284
Topical agent 286, 287, 288
Tannins Caries prevention 221, 224, 289, 298,
299
athymic nude mice also displayed promi- diet containing no tannic acid. The low-den-
nent nucleolar alterations in response to tan- sity lipoprotein cholesterol (LDLC)/ high-
nic acid treatment.272 density lipoprotein (HDLC) ratio is also
Tannic acid and other flavonoids such as lower in RAIF and RICO rats fed a high-fat
luteolin, kaempferol, and apigenin had been diet with tannic acid than the high-fat con-
reported to exert potential inhibition on hy- trol diet. The lower ratio is desirable because
aluronidase, which depolymerizes the major of the lower risk in developing atherosclero-
constituents (hyaluronic acid) of animal con- sis.274 Tannic acid was also reported to cause
nective tissues. Therefore, tannin acid, when favorable decreases in serum lipid param-
given subcutaneously in mice at 1.12 to 2.4 eters in spontaneous hypertensive (SHR) and
mg/kg, was able to neutralize in a dose- normotensive Wistar Kyoto (WKY) rats.275
related fashion the hemorrhage induced by Recent studies of Ong et al.276 showed that
the venom of Crotalus adamenteus (eastern tannic acid inhibited insulin-stimulated lipo-
diamondback rattlesnake). Tannic acid was genesis in rat adipose tissue in vitro with an
also reported to significantly reduce venom- IC50 of about 350 µM. However, gallic acid
induced elevation of blood creatine kinase did not show a similar inhibitory effect at
activity and prolong the surviving time of concentrations up to 1 mM. Even though
mice when injected immediately after the tannic acid was shown not to directly inhibit
administration of venom.273 the binding of insulin to the receptor, it
Yugarani et al.274 studied the effects of inhibited insulin-stimulated autophos-
tannic acid on serum and liver lipids of ge- phorylation of insulin receptor and receptor-
netically hypercholesterolemic (RICO) and associated tyrosine kinase phosphorylation
normocholesterolemic (RAIF) male rats. of RR-SRC peptide.276
RICO and RAIF rats had a lower level of The binding property of tannic acid with
serum lipid when fed a high-fat diet supple- macromolecules makes it instrumental for
mented with tannic acid than the high-fat studying the adhesion between plasma mem-
444
branes with other membranes involved in pneumonitis caused by birds have been well
close apposition of adjacent membrane sur- documented. Craig et al.282 reported that tan-
faces. Kalina and Pease277 showed that tannic acid did not effectively reduce bird anti-
nic acid forms a “complex” with multi- gen levels from homes in which birds were
lamellar vesicles of phosphatidylcholine (PC) previously kept.
and sphingomyelin that can be stabilized with Because of its capability to bind protein
OsO4 so that the membranes survive the etha- and red blood cells, tannic acid has also been
nol dehydration conventionally used in elec- used as a reagent for passive hemagglutina-
tron microscopy. Schrijvers et al.278 found tion test, a sensitive immunological tech-
that the addition of tannic acid caused nique with a wide range of applications.283,284
unilamellar vesicles to aggregate and form Davina et al.285 used the binding capacity of
large multilamellar vesicles. Simon et al.279 tannic acid to stain cell surface carbohy-
demonstrated that tannic acid promoted drates in normal, premalignant, and malig-
vesicle aggregation by reducing the fluid nant epithelium of uterine cervix. Because
spacing between bilayers through the forma- tannic acid deposits within the deep interme-
tion of transient interbilayer bridges by in- diate zone, the differentiating binding of tan-
serting its digallic acid residues into the in- nic acid with cellular components can be
terfacial regions of adjacent bilayers and used to discriminate between cells in normal
spanning the interbilayer space. squamous epithelium, and morphologically
Marzo et al.280 investigated the effects of normal cells in juxtaposition, with lesional
tannic acid on the immune responses of grow- areas in premalignant and malignant epithe-
ing chicken by feeding them 25 or 30 g of lium. This might serve as a reliable cyto-
tannic acid per kg of diet. The added tannic logical diagnosis for cerevical epithelial neo-
acid reduced the weight of bursa of Fabri- plasia.
cius, thymus, and spleen. The levels of total Tannic acid had been used as a topical
IgM and IgG (primary and secondary im- agent in treating burns.286 Davidson’s publi-
mune responses) against Brucella abortus cation in 1925 stimulated the widespread
were reduced in tannic acid-fed chickens. use of tannic acid in Western medicine.287
The numbers of total white blood cells and Recent experimental and clinical investiga-
absolute lymphocytes were also reduced. It tions have proven that tannic acid, when
is concluded that tannic acid affected in a used alone as a topical agent or in combina-
dose-dependent manner the immune function with other drugs, would produce many
tion of growing chickens.280 Miyamoto et advantageous effects, including pain reduc-
al.178 reported that agrimoniin isolated from tion, rapid hemodynamic stabilization, de-
medicinal plant Agrimonia pilosa Ledeb was layed primary excision, early mobilization,
a novel immunomodulatory substance. and good cosmetic effect.288
Agrimoniin induced the cytotoxic effects of
peritoneal exudate cell (PEC) and enhanced
natural killer (NK) cell activity. IX. RESEARCH PERSPECTIVE
Tannic acid has been reported to reduce
allergen levels in house dust and is marketed The implication of food tannins on hu-
for that purpose as the 1 or 3% solution.281 man health is a public concern. Tannins seem
Woodfolk et al.281 found that tannic acid was to be a sword of double edges. On one hand,
very effective in reducing mite allergens from it has preventive benefits (anticarcinogenic
carpet dust, but less effective in reducing cat and anitimutagenic) to health, but on the
allergens at home. Allergic diseases such as other hand, it may be involved in cancer
asthma, allergic rhinitis, and hypersensitive promotion or antinutritional activity. How-
445
ever, the dose of tannins required to induce as grapes or strawberries, the antimicrobial
cancers is probably far beyond the level en- activity of tannic acid is lost. This is a good
countered during normal food intake. There- natural defense mechanism against microbial
fore, tannins are not believed to be potent infection of fruits. Should this system be ma-
carcinogens. There is also a possibility that nipulated properly, we will be able to utilize
the active components responsible for initia- these compounds in extending the shelf-life
tion of carcinogenesis is not tannins them- of certain food products. For example, the
selves, but rather the components associated hydrolysis of tannic acid can be manipulated
with tannins or other social factors such as to match the commercial readiness of fruit for
social classes and smokings. However, consumption, or it could be added to food
tannins at high dosage may act as co-car- product to extend the shelf life.
cinogens or promoters to potentiate some Huang et al.294 tested the antibacterial
skin carcinogens by increasing their solubil- effect of tannic acid, gallic acid, and propyl
ity or diffusibility. Further research is needed gallate on psychrotrophic bacteria in catfish
to identify the roles of the associated active fillet stored at refrigerated temperatures. Pro-
components in initiating carcinogenesis and pyl gallate showed antibacterial activity
the mechanism(s) involved. against psychrotrophic bacteria. Tannins also
Likewise, the antinutritional effects of affect microbial population in many habi-
tannins and their associated components re- tats, including human gastrointestinal tract
quire further study. Tannins are of nutri- and fish ponds (Chung et al., unpublished
tional concern for people whose diets de- results). Our results indicated that tannins
pend largely on crops with high tannin inhibited the growth of fish pathogens and
contents. It is not advisable to ingest a large off-flavor-producing microorganisms,231,232
quantity of high tannin-containing foods; which threaten the aquaculture farming in
tannins affect protein absorption and me- the southeast of the U.S.295,296 The use of
tabolism. tannins to control the population of fish
It is worth noting that tannic acid, ellagic pathogens and off-flavor-producing micro-
acid, gallic acid, and methyl gallate have organisms in aquacultural farms could be of
been used as antioxidants.289,290 Propyl gal- potential commercial importance.
late is also a certified food additive used as Further research is needed to investigate
an antioxidant.291 Tannic acid is categorized the mode of actions of tannins against mi-
as a generally recongized as safe (GRAS) croorganisms, particularly the structure-ac-
food additive292 and is allowed for use at tivity relationship of each tannin component.
400 ppm in frozen dessert/mixed soft can- Tannins form chelates with metal ions and
dies; 150 ppm in non-alcoholic beverages are therefore different from smaller phenols.
and basal gelatins, puddings and fillings; Although Chung et al.230,293 noticed that es-
130 ppm in hard candies; 100 ppm in baked ter linkage of phenolic acids with a polyol,
goods and baking mixes; and 10 ppm in which is usually glucose, is important for the
meat products.292 antimicrobial activity of tannins, the antimi-
Chung and Murdock293 claimed that es- crobial potency of tannins does not correlate
terification is important for the antimicro- linearly with their molecular sizes.252–254 The
bial activities of tannic acid and its related understanding of the mechanism(s) involved
compounds in protecting plants against mi- in antimicrobial activity of each tannin com-
crobial infections. When tannic acid is hy- ponent and determination of the synergistic/
drolyzed, the ester bond is broken. As gallic antagonistic effects of these components will
acid or ellagic acid is released during ripen- improve the opportunity for applying tannins
ing of tannin-containing plants or fruits, such to the food system.
446
Many anticariogenic drugs isolated from complex polyphenolic substrates are ab-
natural herbs are tannins or tannin-like com- sorbed from the gut. The lack of precise
pounds.221,222,224,297,298 Recently, Yu et al.299 understanding of the fate of these compounds
used tannin-fluoride mixture (Ta-F, 0.5% in the human body constitutes a major weak-
tannic acid, 450 ppm fluoride, pH 5.9) for ness in using tannins for a medical purpose.305
caries prevention and found a rather promis- The antimutagenic and anticarcinogenic
ing result. A Ta-F mixture could form a potency of tannins are of great interest to
large columnar deposit and be made dental human health. Therefore, a systematic in-
enamel acid resistant. vestigation is needed to further explore the
Many medicinal herbs contain tannins tannin component for their anticarcinogenic
as part of the biological principles.300–302 potential. Induction of endogenous lipid
Okuda et al.303 have revealed the distribution peroxidation by xenobiotics through genera-
of numerous polyphenolic compounds of tion of free radical species is known to result
different chemical structures in hundreds of in alterations of cellular functions, genotoxic
species of medicinal plants. Several new damages, and tumor initiation.306,307 Lipid
classes of tannins, such as oligomeric hydro- peroxidation resulted in accumulation of vari-
lyzable tannins, including those having ous aldehydes, 308 among which malon-
macro-ring structure, complex tannins, the aldehyde, formaldehyde, and acetaldehyde
condensate with ascorbic acid, caffeic acid are tumorigens, and the DNA adduct of
tetramers, and galloylated proanthocyanidins, malonaldehyde has been detected in hu-
have also been isolated. The chemical struc- mans.309 Recent studies by Ni et al.310 sug-
tures of a few examples of these tannins are gested that the ratios of various aldehydes
shown in Figure 6. Marked biological and formed are influenced by the presence of
pharmacological activities such as inhibition various antioxidants. For example, the accu-
of carcinogenesis, host-mediated antitumor mulation of formaldehyde during lipid
activity, antiviral activity, and inhibition of peroxidation was much higher in the pres-
lipid peroxidation and lipoxygenase, xan- ence of vitamin C. The level of formalde-
thine oxidase, and monoamine oxidase have hyde was decreased by 40% when vitamin E
been found in several of these polyphenolic was co-incubated with vitamin C than vita-
compounds.303 Cragg et al.304 reported that as min C alone. Some tannins are antioxidants.
of August 1993, 21,881 extracts derived from The potential in using tannins to prevent
over 10,500 samples colleced by National lipid peroxidation is worth testing. The pro-
Cancer Institute have been screened for ac- file of aldehydes formation during lipid
tivity against HIV; 2320 of these extracts peroxidation in the presence of tannins has
were of medicinal plant origin. Approxi- not been studied. Tannins may reduce lipid
mately 18% of both the total number of ex- peroxidation or they may interact synergisti-
tracts and the medicinal plant-derived ex- cally with other antioxidants such as vitamin
tracts showed significant anti-HIV activity; C or E to affect lipid peroxidation and ulti-
in each instance about 90% of the active mately exert their influence on the carcino-
extracts were aqueous. The activity of the genicity and/or mutagenicity of these
aqueous extracts has been attributed mainly xenobiotics.
to tannins or polysaccharides.304 In a recent Tannins and their related compounds may
review discussing tannins as potential drugs, inhibit the metabolic enzymes of xenobiotics.
Haslam305 pointed out that the anti-HIV ac- Khan et al.311 showed that GTP produced in
tivity of various galloyl and hexahydroxy- vitro inhibition of cytochrome P-450 mixed
diphenoyl esters increased with molecular function oxygenases, enhancement of phase
size. However, it is not clear how or if these II enzymes glutathion-S-transferase and
447
FIGURE 6. Some pharmacological tannins isolated from medicinal plants. (From Okunda et al., 1992.)
quinone reductase, and enhancement of the that tannic acid and its related compounds
antioxidant enzymes glutathione peroxidase are inhibitory to nitroreductase of several
and catalase. Chung et al. also demonstated intestinal bacteria (unpublished result).
448
In summary, tannins present in varying 6. Price, M. L. and Butler, L. G., Tannins and
concentrations in foods have profound ef- Nutrition. Purdue Univ. Agric. Exp. Stn. Bull.
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Critical Reviews in Food Science and Nutrition

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Tannins and Human Health: A Review

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Tannins and Human Health: A Review

Compound Type of tumors Ref.

Chlorogenic acid 166

Compound Mutagen Ref.

Epigallocatechin, B[a]P 184

Fungi species Tannin Ref.

Botrytis cinerea Condensed tannins 197

Yeast species Tannin Ref.

Candida albicans Water and ethanol extracts 226

inhibited by 2,3,4-tetrakis(3,4,5-trihy- to be inhibited by the leaf extracts of Aesculus

Bacterial species Tannin Ref.

Aeromonas hydrophila Tannic acid, propyl gallate 231

Bacterial species Tannin Ref.

Proteus vulgare 2,3,4-tetrakis-(3,4,5– 216

Bacterial species Tannin Ref.

Streptococcus pneumonia Tannins 210

Streptococcus sobrinus PGG, condensed tannin, 221, 222, 223

Name of viruses Tannin Ref.

Coxsackie virus, Tannins (fruits) 239

Tannins Effect Ref.

Agrimoniin Immune response 178

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