International Research Council on Food,

Nutrition, and Cancer

A Review of the Health Effects of Green Tea Catechins in

In Vivo Animal Models1
Vanessa Crespy and Gary Williamson2
Nestle Research Center, Vers Chez Les Blanc, CH-1000 Lausanne 26, Switzerland.

KEY WORDS: green tea

cardiovascular disease

catechin

epigallocatechin gallate

Tea is one of the most popular beverages consumed worldwide. Tea, from the plant Camellia sinensis, is consumed in
different parts of the world as green, black, or oolong tea.
Green tea is favored in Japan and China, and initial research
on the benefits of green tea was carried out in these countries
because of local customs. Tea contains many compounds,
especially polyphenols, and epidemiological studies show that
polyphenolic compounds present in tea reduce the risk of a
variety of diseases (1 4).
Green and black tea are processed differently during manufacturing. To produce green tea, freshly harvested leaves are
steamed to prevent fermentation, yielding a dry, stable product. Catechins are the main compounds in green tea; they
consist of ()-epicatechin, ()-epicatechin-3-gallate (ECg),3

in vivo animal studies

cancer

()-epigallocatechin, and ()-epigallocatechin-3-gallate

(EGCg) (5). To produce black tea, the fresh leaves are allowed
to wither, decreasing their moisture content, until their weight
is 55% of the original leaf weight. The withered leaves are
then rolled and crushed, initiating fermentation of polyphenols. This fermentation converts catechin to theaflavins and
thearubigins, consequently decreasing the catechin content.
Many in vitro studies on catechins report mechanisms
consistent with protection against degenerative diseases (6
9). Nevertheless, many of these studies used high concentrations of catechin and thus do not reflect typical catechin
concentrations found in animal or human plasma. It is difficult
to extrapolate these results to in vivo situations. Moreover,
nongalloylated catechins are present in plasma as conjugated
forms (10 12), except for EGCg and ECg, which are significantly unconjugated (13). However, because of the lack of
conjugated forms as standards or test compounds, it is not
possible to test the in vitro biological effects of the conjugates.

1
Published in a supplement to The Journal of Nutrition. Presented as part of
the International Research Conference on Food, Nutrition, and Cancer held in
Washington, DC, July 1516, 2004. This conference was organized by the American Institute for Cancer Research and the World Cancer Research Fund International and sponsored by BASF Aktiengesellschaft; Campbell Soup Company;
The Cranberry Institute; Danisco USA Inc.; DSM Nutritional Products, Inc.; Hills
Pet Nutrition, Inc.; Kellogg Company; National Fisheries Institute; The Solae
Company; and United Soybean Board. An educational grant was provided by The
Mushroom Council. Guest editors for this symposium were Helen A. Norman, Vay
Liang W. Go, and Ritva R. Butrum.
2
To whom correspondence should be addressed.
E-mail: gary.williamson@rdls.nestle.com.
3
Abbreviations used: AOM, azoxymethane; CYP, cytochrome P450; DENA,

diethylnitrosamine; DMBA, 7,12-dimethylbenz[a]anthracene; DMH, dimethylhydrazine; ECg, ()-epicatechin-3-gallate; EGCg, epigallocatechin gallate; ENNG,
N-ethyl-N-nitro-N-nitrosoguanidine; GTE, green tea extract; IQ, 2-amino-3methylimidazol(4,5-f)quinoline; MNNG, methyl-N-nitro-N-nitrosoguanidine; NNK,
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; PGI2, prostacyclin I2; SOD, superoxide dismutase; TRAMP, transgenic adenocarcinoma of the mouse prostate;
TXA2, thromboxane A2; UDP-GT, UDP-glucuronosyltransferase.

0022-3166/04 $8.00 2004 American Society for Nutritional Sciences.

3431S

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ABSTRACT There is good evidence from in vitro studies that green tea catechins have a role in protection against
degenerative diseases. However, the concentrations used in vitro are often higher than those found in animal or
human plasma, and so in vivo evidence is required to demonstrate any protective effect of catechins. This article
summarizes the most interesting in vivo animal studies on the protective effects of green tea catechins against
biomarkers for cancer, cardiovascular disease, and other degenerative diseases. Generally, most studies using
animal models show that consumption of green tea (catechins) provides some protection, although most studies
have not examined dose response. Tea catechins could act as antitumorigenic agents and as immune modulators
in immunodysfunction caused by transplanted tumors or by carcinogen treatment. Green tea has antiproliferative
activity in hepatoma cells and hypolipidemic activity in hepatoma-treated rats, and some studies report that it
prevents hepatoxicity. It could act as a preventive agent against mammary cancer postinitiation. Nevertheless, the
implications of green tea catechins in preventing metastasis have not been clearly established. Long-term feeding
of tea catechins could be beneficial for the suppression of high-fat dietinduced obesity by modulating lipid
metabolism, could have a beneficial effect against lipid and glucose metabolism disorders implicated in type 2
diabetes, and could also reduce the risk of coronary disease. Further investigations on mechanisms, the nature of
the active compounds, and appropriate dose levels are needed. J. Nutr. 134: 3431S3440S, 2004.

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TABLE 1
Summary of studies on effects of green tea catechins on cancer in animal models
Ingested
dose/d

EGCg
equivalent Species

Stress

Duration Subjects/
d
group

28

2
2
2
2
2

Oral tumor burden

Dysplasia and oral carcinoma
Micronuclei formation
Proliferating cell nuclear antigen
Number of oral tumors

2
2
2
2

Volume of oral tumors

Squamous cell carcinoma
Duodenal tumors
Duodenal tumors

GTE (1.5%,
wt:v)

Hamster

DMBA (0.5%)

105

16

GTE (6 g/L)

Hamster

DMBA (0.5%)

126

15 mg/kg
3.7 mg/kg

Mouse
Mouse

ENNG (100 mg/L)

ENNG (100 mg/L)

84
84

Not given
Not given

5 mg/kg
50 mg/kg

Mouse
Rat

ENNG (100 mg/L)

MNNG (80 mg/L)

84
112

Not given
Not given

GTE (0.01%)
GTE (0.1%)
Green tea
(2%, wt:v)

1.8 mg/kg
18 mg/kg

Rat
Rat
Rat

AOM (7.4 mg/kg)

AOM (7.4 mg/kg)
DMH (20 mg/kg)

112
112
224

Not given
Not given
42

GTE (0.05%,
wt:v)
GTE (0.1%)

Rat

DMH (100 mg/kg)

10

20

Rat

DMH (40 mg/kg)

231

21

GTE (0.05%,
wt:v)
GTE (2%,
wt:v)

Rat

DMH (25 mg/kg)

10

Rat

DMH (20 mg/kg)

112

15

GTE (50 mg/

kg)

Rat

Azoxymethane
(74 mg/kg)

112

20

Mouse

NNK (56 mol/

kg)
NNK (100 mg/kg)

91

25

91

25

252

280

15

280

15

56 mg/kg

Mouse

Green tea
(0.63%,
wt:v)

122 g/L

Mouse

NNK (56 mol/

kg)
Subcutaneous
injection
LL2-Lu3 cells
(106)
Lewis lung
carcinoma
transplantation
DENA (50 g/kg)

Green tea
(1.25%,
wt:v)

245 g/L

Mouse

DENA (50 g/kg)

Green tea

56 mg/kg

Mouse

0.56 mg/
mL

Mouse

GTE (1%,
wt:v)

Mouse

2 Duodenal tumors
2 Incidence of gastric carcinogenesis;
number of adenocarcinomas,
adenomas, adenomatous
hyperplasias
2 Colon tumors
2 Colon tumors
2 Aberrant crypt foci
2 Number of tumors
2 Tumor volume
2 Proliferating cell nuclear antigen
2 Ras-p21 and Bcl-2 expression
1 Bax expression
2 Colonic mucosal lipid
hyperoxidation
1 Volume of intestinal tumors

Biomarkers not
affected

14

Microvessel
density

15

16
16
16
16

16
16
17

18
Multiplicity and/or
incidences of
intestinal
adenomas
Multiplicity and
incidences of
intestinal
carcinomas

19

2 DNA damage

20

2 Aberrant crypt foci in intestine

2 Proliferating cell nuclear antigen
2 Ras-p21 expression

21
Colorectal tumors
Incidence of
tumors
Level of dysplasia
Cancer
invasiveness

2 Number of lung tumors

28

22

23

Immune parameters normalized

21

Reference

24

2 Number of lung tumors

23

2 Reduction of lung tumors

Lung tumor weight

25

2
2
1
2
2
2
2
2
2
2
2
2
2
2
2

CD8

24

Lung tumor weight

Thymus weight
CD4
Number of liver tumors
Hepatic adenomas
Number of diameter for tumors
Number and volume of liver foci
Lung adenoma multiplicity
Number of lung adenomas
Number of liver tumors
Hepatic adenomas
Number of diameter for tumors
Number and volume of liver foci
Lung adenoma multiplicity
Number of lung adenomas

26

26

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GTE (0.1%)
GTE
(0.025%)
EGCg
EGCg

GTE (2%,
wt:v)
GTE (1%,
wt:v)
EGCg (wt:v)

Biomarkers affected

GREEN TEA CATECHINS IN ANIMAL MODELS

Ingested
dose/d

EGCg
equivalent Species

GTE (0.1%,
wt:v)
GTE (1%)

0.085%

Stress

Duration Subjects/
d
group

DENA (200 mg/kg)

70

10

Rat

DENA (200 mg/kg)

42

13

Rat

2-NP1 (120 mg/kg)

14

410 g/L

Rat

2-NP (100 mg/kg)

14

Green tea
(0.5%, wt:
v)
GTE (2%,
wt:wt)

12.4%

Rat

Aflatoxin (25 mg/

kg) CCl4 (0.8

24

12

Rat

Subcutaneous
injection of
AH109A cells
(105)

14

10

GTE (0.1%,
wt:v)

0.085%

Rat

Choline-deficient
diet

70

10

GTE (0.5% of
diet)

0.29%

Rat
DMBA (50 mg/kg)
(female)

161

14

EGCG (0.5%)

0.4%

Rat
DMBA (50 mg/kg)
(female)

161

14

GTE (1%)

Rat
DMBA (25 mg/kg)
(female)

252

20

EGCg (1%)

Nude
Transplantation
mouse
RIII/MG cells (105)
Rat
(female)

140

119

15

168

10

GTE (2%,
wt:v)
Green tea
(2%, wt:v)

GTE (0.3%,
wt:v)
GTE (0.1%,
wt:v)

mL/kg)

.62 mg/kg TRAMP

mouse

Biomarkers not
affected

Reference

2 Liver DNA damage during

carcinogenesis
1 Liver weight
2 Glutathione S-transferase
2 Cell proliferation in the liver

27

2
2
2
2
2
2
2
2
1
2
2
2
1
1
2

30

Lipid peroxide levels

Lactate dehydrogenase
Alanine amino transferase
Glutathione S-transferase (liver)
Lipid peroxide level (liver)
Fibrosis
Weight of liver primary tumor
Total plasma cholesterol
HDL cholesterol
VLDL LDL cholesterol
Atherogenic index
Serum triglycerides
Excreted fecal biliary feces
Weight of dried feces
Liver DNA damage during
carcinogenesis

2 Total mammary tumors

28
29
29

31
Serum lipid
peroxide

32

Liver tissue
damage
Plasma alanine
aminotransferase
Multiplicity of
mammary
tumors
Multiplicity of
mammary
tumors
Size mammary
tumors
Induction of
histopathological
mammary
tumors
Body weight

27

33
33
34

2 Growth of precancerous RIII/MG

35
cells
No tumor formation
36
1 Latency of first mammary tumors
Number of
2 Mammary tumor weight
noninvasive
2 Number of invasive mammary
mammary
malignant tumors
malignant tumors
2 Prevention or delay of prostate
37
cancer development
2 Growth of prostate tumor
2 Prostate weight
2 Genitourinary organ weight
2 Number of apoptotic cells in prostate
2 Life expectancy

1 Abbreviation: 2-NP, 2-nitropropane.

Thus, animal studies are more relevant for investigating the

physiological effects of catechins, but in vitro studies often
provide more mechanistic information. This article summarizes the most interesting in vivo animal studies of the biological effects of green tea on biomarkers of chronic disease risk.
In vivo studies of green tea and cancer
Many experimental animal studies using biomarkers of cancer risk or cancer development have tested green tea extract
(GTE) or EGCg. Many of these studies report that GTE or
EGCg protects against chemical carcinogens in various organs
such as intestine, lung, liver, prostate, and breast (see Table 1
for a summary).
Effects on oral and gastrointestinal cancer. Hamsters
were treated with topical 7,12-dimethylbenz[a]anthracene
(DMBA) to induce oral tumors in the buccal pouch (14,15).
Oral administration of green tea before and until the end of

the experiment reduced the mean tumor burden, including the

incidence of dysplasia and oral carcinoma (Table 1).
N-ethyl-N-nitro-N-nitrosoguanidine (ENNG) and azoxymethane (AOM) cause intestinal or colorectal tumors after
chronic administration. Green tea (0.12.0% of diet) decreased the number of duodenal or colon tumors induced by
the various promoters (16). Dietary ingestion of EGCg, the
main compound present in green tea, also decreased the incidence of duodenal tumors (Table 1). In parallel, ingestion of
EGCg by rats decreased the incidence of gastric carcinogenesis
induced by methyl-N-nitro-N-nitrosoguanidine (MNNG)
(Table 1). These findings suggest that green tea catechins and
EGCg are useful in preventing gastrointestinal carcinogenesis.
Nevertheless, a study performed under similar conditions
(with AOM pretreatment and then green tea administration)
found that green tea had no effect on colorectal carcinogenesis, but this could be due to differences in ingestion during the
studies (22) (Table 1).

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Rat

Biomarkers affected

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Effects on liver cancer. DENA also induces tumors in the

liver. Animals treated with DENA and green tea at different
concentrations showed a marked decrease in liver tumors
(diameter, number, number, and volume of liver foci) (Table
1) (26,28,32). As discussed above, this suggests a possible
association between the chemopreventive activity of tea on
lung tumors and the concentration of EGCg in tea, but there
was no apparent relation between EGCg and liver tumor
response.
In the same model, green tea reduced oxidative DNA
damage in mice (27) and rats (29,30). The authors suggest that
green tea may be a chemopreventive agent for hepatocarcinogenesis in the absence of chronic hepatocyte damage. Similar
results were reported in animals treated with aflatoxin; green
tea inhibited initiation and promotion steps (Table 1) (31).
Moreover, daily ingestion of green tea prevented hepatotoxicity (increase in serum glutamic-oxaloacetic transaminase and
glutamic-pyruvic transaminase; decrease in hepatic glycogen,
serum triglyceride, and lactate dehydrogenase) (Table 1) and
cell proliferation in the liver in rats after administration of
2-nitropropane (29,30).
Choline deficiency causes chronic hepatocyte damage in
mice, which mimics tumor development in cirrhotic liver
tissue. In this model, green tea did not protect against liver
tissue damage as assessed by either histology or plasma marker
enzyme levels (Table 1). This suggests that green tea might
have limited potential to inhibit tumor development in cirrhotic liver tissue. Biological variables were measured after
implantation of hepatoma cells in rats with and without ingestion of green tea (32). Green tea markedly suppressed
hepatoma-induced hyperlipidemia (hypercholesterolemia and
hypertriglyceridemia) (Table 1). Moreover, green tea increased biliary secretion into feces.
These results suggest that green tea has an antiproliferative
activity on hepatoma cells, has hypolipidemic activity in hepatoma-treated rats, and also prevents hepatoxicity.
Effects on mammary cancer. The effects of green-tea
catechins on mammary cancer were tested in DMBA-treated
female rats (33,34) (Table 1). Green tea or EGCg exhibited
chemopreventive action on DMBA-induced mammary carcinogenesis only when given in the postinitiation stage, and the
effect was not dose dependent. Indeed, green tea ingestion
markedly increased the mean latency of tumors and reduced
the tumor burden and the number of invasive tumors in rats
with DMBA-induced mammary carcinogenesis (36). Green
tea administered at the time of transplantation had a similar
effect on transplanted mammary cells in mice (Table 1) (36).
These results suggest that green tea could act as a preventive
agent against mammary cancer postinitiation. Further investigations are required to establish the mechanisms of action,
the nature of the active compounds, and the appropriate dose
levels.
Effects on prostate cancer. Transgenic adenocarcinoma
of the mouse prostate (TRAMP) is one model for prostate
cancer that closely mimics progressive forms of the disease in
humans. Green tea inhibits the growth and the progression of
prostate cancer in such mice (Table 1), and furthermore
inhibits metastasis of this cancer to distant organ sites (lymph,
lungs, liver, and bone) (37).
Regarding the biological effects of green tea against various
cancers, catechin may be a chemopreventive agent at the early
stages. Nevertheless, the implications of green tea catechins in
preventing metastasis have not been clearly established.

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Other parameters, such as histological assessment or expression of specific genes, can be measured in animal models of
colorectal cancer. Aberrant crypt foci appear in the colonic
mucosa of carcinogen-treated animals and represent precursor
lesions of chemically induced colon cancer. This assessment
permits evaluation of the role of nutritional components and
screening of potential new chemopreventive agents. Green tea
inhibits aberrant crypt foci and colorectal cancer induced by
dimethylhydrazine (DMH) in rats (17,21). 8-Hydroxydeoxyguanidine is a product of DNA damage by oxygen radicals.
DNA damage causes misreading of DNA bases, leading to
mutagenesis and carcinogenesis; therefore, 8-hydroxydeoxyguanidine is speculated to be a biomarker of oxidative stress
related carcinogenesis. The administration of green tea
inhibits DNA damage, as shown by a decrease in 8-hydroxydeoxyguanidine production, suggesting that green tea
reduces mutagenesis and carcinogenesis (Table 1) (18,20).
Moreover, the activation of ras p-21 represents one of the
earliest and most frequently occurring genetic alterations associated with human cancer. Oral feeding with a diet containing 2% green tea suppresses the DMH-induced expression of
ras p-21.
Two important mechanisms of action of green tea may be
inhibition of cancer cell proliferation and induction of apoptosis. After ingestion, green tea catechins are present as
native forms in the digestive tract. Because they are not
completely absorbed by the gut (38), catechins can be present
at high concentrations in the intestinal lumen and in this way
can interact directly with duodenal or colon tumors by influencing apoptosis and proliferation.
Effects on lung cancer. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is generally used to induce lung tumorigenesis. Ingestion of green tea (2% of diet) decreased the
number of lung tumors induced by NNK in mice, compared
with a control group that was not treated with tea (23) (Table
1). This result was confirmed by another experiment in which
mice were subcutaneously injected with Lewis lung carcinoma
cells (25). Peroral administration of a green tea infusion markedly reduced the number of lung tumors.
An equivalent experiment was conducted with EGCg at the
concentration found in green tea (Table 1). The number of
tumors decreased, but the decrease was less than with green tea.
These observations suggest that EGCg, the major compound of
tea, could be the principal but not the only compound responsible
for the decrease in tumorigenesis. EGCg might interact synergistically or additively with the other catechins present in green tea,
but this has not been demonstrated.
Diethylnitrosamine (DENA) induces lung tumors when
injected. Ingestion of green tea during DENA treatment decreased the number of lung tumors in mice at all dosages
(Table 1) (26). This suggests a possible association between
the chemopreventive activity of tea on lung tumors and the
concentration of EGCg in tea.
Treatment with DENA altered immune functions in mice:
suppressive modulation, such as humoral immunity and cell
immunity, and enhanced modulation, such as nonspecific
phagocytosis. Ingestion of green tea returned these immune
functions to basal levels (24). Moreover, the transplantation of
Lewis lung carcinoma cells into mice decreased the CD4positive T lymphocytes and CD4:CD8 ratio. Ingestion of
green tea improved immune functions and inhibited tumor
growth (24).
These results show that tea catechins could act as antitumorigenic agents and as immune modulators in immunodysfunction caused by transplanted tumors or by carcinogen treatment.

GREEN TEA CATECHINS IN ANIMAL MODELS

Cardiovascular diseases and green tea

Zucker rats (which are genetically obese), injection of streptozotocin or alloxan (which destroys pancreatic cells), and
treatment with sucrose-rich diets (which induces obesity and
insulin resistance).
In a study in rats treated with alloxan, green tea decreased
serum glucose levels (51), suggesting that catechins interact
with glucose metabolism. Moreover, in an oral glucose tolerance test in normal rats, green tea catechins decreased plasma
insulin levels but did not affect plasma glucose levels (54).
Nevertheless, adipocytes increased glucose uptake, but the
interaction between catechins and glucose metabolism is unclear and should be investigated.
In type 2 diabetes, lipid metabolism is modified: plasma and
liver triglyceride levels and plasma cholesterol levels are elevated. GTE intake reduced these values in both Zucker rats
and rats fed a sucrose-rich diet (52,53). Catechins also reduced
plasma triglyceride levels in an oral glucose tolerance test in
normal rats (54).
These results suggest that green tea catechins could act as
preventive agents and could have a beneficial effect against
lipid and glucose metabolism disorders implicated in type 2
diabetes.
Effects on nephropathy. Diabetes is generally accompanied by nephropathy due to microvascular dysfunction or
impairment. In normal kidney tissue the production of thromboxane A2 (TXA2) and prostacyclin I2 (PGI2) is controlled,
and the balance between them is important to maintain homeostasis in vivo. A modification of the PGI2:TXA2 ratio
accelerates thrombogenesis in the renal tubules, increasing the
risk of impaired function and atherosclerosis. The production
of these compounds depends on the activity of phospholipase
A2 (which is higher in the case of kidney disorders) and the
fatty acid composition. Streptozotocin increases the synthesis
of TXA2 and decreases that of PGI2. Administration of green
tea catechins in rats pretreated with streptozotocin decreases
the synthesis of TXA2 and increases that of PGI2 (47,48) and
so returns the ratio to that of untreated rats (Table 2). Kidney
function is improved by green tea catechin supplementation as
a result of its antithrombogenic action, which in turns controls
the arachidonic acid cascade system. This also demonstrates
that the glomerular filtration rate is increased (Table 2). One
study examined blood variables of glomerular filtration (protein excretion, glucose excretion, and blood nitrogen) in rats
treated with cisplatin, a nephropathy inducer (50). Because
green tea did not affect the excretion of protein and glucose in
urine, the blood nitrogen level was markedly decreased (Table
2). Moreover, in the kidney, SOD and catalase activities were
decreased and increased, respectively. Thus, green tea catechins appear to reduce oxidative stress in the kidney.
Effects on vascular disease. Pathogenesis of vascular diseases such as atherosclerosis is 2 to 6 times higher in diabetic
subjects than in normal subjects. Green tea catechins normalized the PGI2:TXA2 ratio in rats treated with streptozotocin
and also suppressed phospholipase A2 and cyclooxygenase
activities (49). These results show that green tea catechins
have antithrombotic effects in these models.
Other effects of green tea catechins
Effects on absorption of ions. Tea catechins can affect iron
absorption, particularly in groups at risk of iron deficiency
(56,57), but their effects on other ions are poorly defined. Green
tea ingestion over a long period does not affect the apparent
absorption of copper, in contrast to that of zinc, which decreases,
and that of manganese, which increases (61) (Table 3). However, catechin intake does not affect the plasma concentration of

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Cardiovascular diseases, principally heart disease and

stroke, are the leading cause of mortality in Western countries
among both men and women in all racial and ethnic groups.
The risk of atherosclerosis is increased by high blood pressure
(hypertension), kidney disorders, obesity, diabetes, smoking,
excessive alcohol consumption, stress, thyroid and adrenal
gland problems, and lipid disorders.
Effects on antioxidant markers and oxidative stress. Antioxidants are compounds that protect cells against the damaging effects of reactive oxygen species, such as singlet oxygen,
superoxide, peroxyl radicals, hydroxyl radicals, and peroxynitrite. An imbalance between antioxidants and reactive oxygen
species results in oxidative stress, leading to cellular damage.
Catechins are hypothesized to help protect against these diseases by contributing, along with antioxidant vitamins (i.e.,
vitamins C and E) and enzymes [i.e., superoxide dismutase
(SOD) and catalase], to the total antioxidant defense system.
In vivo studies show that green tea catechins increase total
plasma antioxidant activity (39,40) (Table 2). Intake of GTE
also increases the activity of SOD in serum and the expression
of catalase in the aorta, enzymes implicated in cellular protection against reactive oxygen species (40,41). This action is
combined with direct action on oxygen species by a decrease
in the nitric oxide plasma concentration (41). Malondialdehyde, a marker of oxidative stress, also decreases after green tea
intake (39,50). These results suggest that catechins could have
a direct (antioxidant) or indirect (increase of activity or expression) effect.
Because catechins can act as antioxidants in vitro, they
might prevent the oxidation of other antioxidants, such as
vitamin E. However, ingestion of green tea catechins does not
modify the plasma status of vitamins E and C in vivo
(40,46,55) (Table 2). Nevertheless, 1 study reports that catechens increase vitamin E concentration in LDL (46) and in
this way could protect LDL against peroxidation (39).
Effects on lipid metabolism. Green tea catechins affect
lipid metabolism by different pathways and prevent the appearance of atherosclerotic plaque (Table 2). GTE intake
decreases the absorption of triglycerides and cholesterol
(42,45), and these findings are in accordance with the fact that
fat excretion increases (42). Nevertheless, the mechanism
remains to be determined. Some studies report that green tea
catechins decrease plasma total cholesterol and blood triglyceride levels, but the effects differ among studies (43,44,46)
(Table 2). This difference could be due to the different animal
models used (i.e., rats, mice, and rabbits) (Table 2). Moreover,
regarding the green tea catechin intake levels in these studies,
plasma cholesterol apparently decreases only when green tea
intake is 0.5% of the diet (Table 2). This suggests that the
effect on plasma cholesterol occurs only at high doses. Nevertheless, green tea ingestion decreases LDL cholesterol (39).
Concurrently, HDL cholesterol increases, showing that green
tea polyphenols exert an antiatherosclerotic effect. This effect
is also reported in apolipoprotein E deficient mice (43).
These results demonstrate that long-term feeding of tea
catechins can be beneficial in the suppression of high-fat
dietinduced obesity by modulating lipid metabolism. By this
mechanism, green tea could possibly reduce the risk of associated diseases, including diabetes and coronary disease.
Effects on carbohydrate metabolism. Type 2 diabetes is a
heterogeneous disorder that involves resistance of glucose and
lipid metabolism in peripheral tissues to the biological activity
of insulin and inadequate insulin secretion by pancreatic
cells. Various animal models and treatments mimic diabetes:

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TABLE 2
Effects of green tea catechins on cardiovascular diseases in animal models
Ingested
dose/d

EGCg eq

Species

Green tea
(3.5 g/L)

SHRSP1 rat

EGCG (1%)

Rat

GTE (0.8 g/L; 584 g/kg

4 mL/d)

Mouse
Apo (E) deficiency

GTE (0.5%,
wt:wt)

Mouse C57BL/6 J

74% of
catechin

Stress

Duration Subjects/
d
group

Dietary
cholesterol
(5 g/kg
diet)

High-fat diet
(300 g/kg
diet)

20

24

98

17

308

Biomarkers affected
2 Systolic and diastolic
blood pressure
1 Catalase expression (aorta)
2 Nitric oxide plasma
concentration
2 Total cholesterol in plasma
2 Hepatic total cholesterol
1 Increase the fat excretion
2 Triglyceride and
cholesterol absorption
1 Body weight
2 Atherosclerotic area

1
GTE (2.5%)

11.6% of GTE Rat

GTE (120
mg)
GTE (3 g/L)

23.8 mg/L

Rat (ovariectomized)

337 mg/L

Rat

Green tea (3
g/L)

10% of green
tea

Rabbit
(hypercholesterolemic)

GTE (0.5%)

51.86% of
GTE

Rat

GTE (0.5%)

GTE (1%,
wt:wt)

Dietary
cholesterol
(10 g/kg
diet)

None

35

35

147

20

Streptozotocin
(55 mg/kg)

28

10

Rat

Streptozotocin
(55 mg/kg)

28

10

45.3% of GTE Rat

Streptozotocin
(55 mg/kg)

28

10

2
1
2
2
2
1
2
2
1
1
1
1
2
1
2
2
2
2
2
1
1

Energy intake
Fecal lipids
Liver triglycerides
Plasma total cholesterol
Plasma glucose
Insulin
Leptin
mRNA expression of acylCoA oxidase
mRNA expression of
medium-chain acyl-CoA
dehydrogenase
LDL peroxidation
Serum antioxidant capacity
Total plasma cholesterol
Plasma free cholesterol
LDL cholesterol
HDL cholesterol
Cholesterol absorption
-Tocopherol absorption
GSH peroxidase (liver)
GSH (liver)
Vitamin A (liver)
Total antioxidant status
(liver)
MDA (liver)
SOD activity (serum)
GSH peroxidase (serum)
MDA (serum)
SOD activity (brain)
GSH peroxidase (brain)
MDA (brain)
Plasma vitamin A
LDL vitamin E

Reference

Urinary nitric oxide

excretion

41

Liver lipid
concentration

42

Plasma cholesterol
Plasma
triglycerides
Liver cholesterol
Plasma
triglycerides

43
44

39

45
SOD activity (liver)
Vitamin E (liver)
Vitamin C (liver)
-Carotene (liver)
Vitamin E (serum)
Vitamin A (serum)
Vitamin C (serum)
-carotene (serum)
Vitamin E (brain)
Vitamin A (brain)
Vitamin C (brain)
-Carotene (brain)
Serum cholesterol,
LDL cholesterol,
and lipids
Vitamins E and C
Total antioxidant
activity of
plasma
Lipids peroxidation
Aortic
atherosclerotic
lesions

2 Production of thromboxane
A2 (kidney)
1 Prostacyclin formation
1 Glomerular filtration rate
2 Kidney microsomal
Phospholipase A2
concentration
activity
Production of
1 Kidney microsomal
thromboxane
hydrolysis of
phosphatidylethanolamine
1 Phospholipase A2 activity
1 Cyclooxygenase activity
2 Concentration of platelet
thromboxan B2
1 Aortic prostaglandin F1

40

46

47

48

49

Downloaded from jn.nutrition.org by guest on December 6, 2014

2
2
2
2
2
2
2
1

Biomarkers not
affected

GREEN TEA CATECHINS IN ANIMAL MODELS

Ingested
dose/d

EGCg eq

Species

Stress

Duration Subjects/
d
group

Biomarkers affected

Rat

Cisplatin

40

2
2
2
2
2
1

Blood urea nitrogen

Serum creatinine
Serum malondialdehyde
Kidney
SOD activity
Catalase activity

GTE (100 mg/

kg)

Rat

Alloxan (120
mg/kg)

15

GTE (130 mg)

Zucker rat

10

2
2
2
1
2
2
2

Serum glucose level

Lipid peroxidation
Level creatinine
SOD
Body weight
Liver weight
Epidymal, perirenal, and
mesenteric adipose weight
Total plasma cholesterol
Total plasma protein
Liver triglycerides
Plasma total triglycerides
Plasma total cholesterol
Liver triglycerides
Heart cholesterol
Plasma insulin level
Plasma free fatty acids level
Plasma triglyceride level
Glucose uptake by
adipocytes

GTE (1%, wt: 20.16% of

wt)
extract

Rat

Sucrose-rich
diet (580
g/kg diet)

25

GTE (0.5%,
wt:v)

Rat

Oral glucose
tolerance
test

84

199.49 g/kg

2
1
2
2
2
2
2
2
2
2
1

Biomarkers not
affected
Reference
Urinary protein
excretion
Urinary glucose
excretion
Glutathione
peroxidase
activity

50

51

Plasma
triglycerides
Liver total
cholesterol

52

HDL cholesterol
Liver cholesterol
Heart triglycerides

53

Plasma glucose
level

54

1 Abbreviations: GSH, glutathione; MDA, malonyl dialdehyde; SHRSP, spontaneously hypertensive stroke-prone.

these ions (60). Green tea catechins have the potential to affect
absorption and metabolism of ions because flavonoids interact
with a variety of metal ions (66).
Effects on drug-metabolizing enzymes. Long-term ingestion of green tea increases UDP-glucuronosyltransferase
(UDP-GT) activity in rats (62,63,65), and after being absorbed, catechins are metabolized by drug-metabolizing
enzymes in various organs (67 69). Thus, the increased glucuronidation through UDP-GT induction is postulated to contribute to the anticarcinogenic effect of green tea by facilitating the metabolism of chemical carcinogens into inactive
products that are readily excreted. The interaction between
2-amino-3-methylimidazol(4,5-f)quinoline (IQ) and green tea
catechin metabolism was examined (64). IQ is a precarcinogen that was originally detected in an extract of fried meat.
The major route of IQ biotransformation in rats is cytochrome
P450 in a first step, followed by conjugation to a sulfate and a
glucuronide conjugate. Green tea modifies IQ metabolism in
rats, increasing the formation of IQ glucuronides, which are
then excreted in the urine (Table 3). Moreover, protection
against cancers induced by polycyclic aromatic hydrocarbons
by green tea catechins may be due to the inhibition of their
cytochrome P450 (CYP) metabolism, but the effect of green
tea on CYP enzymes depends on the particular form. Indeed,
long-term consumption of green tea increases CYP1A1 and
1A2 activities, but not 2B1 and 2E1 activities, in normal rats
(Table 3). Also, it is difficult to draw conclusions about a
beneficial effect of green tea against carcinogens involving
only modulation of this metabolic pathway.
Effects on hormone metabolism. At a high dose (5% of
diet for 13 wk), GTE induced a thyroid enlargement (goiter)
in normal rats (58,59). This high-level treatment modified the
plasma concentrations of the thyroid hormones (Table 2).
However, drinking even a very high dietary amount of green
tea would be unlikely to cause these types of effects.

Conclusions
Studies demonstrate biological effects with ingested doses
of green tea or EGCg ranging from 0.01 to 2.5% of the diet.
Different preparation methods were employed: 1) green tea
was prepared with fresh leaves infused in hot water, filtered,
and given to the animals as a drink; 2) GTE was dissolved in
the drinking water; 3) GTE was mixed with the diet; and 4)
EGCg was added to the drinking water or to the diet. These
preparation methods influence the catechins both quantitatively and qualitatively; the amount of catechins also varies in
the original tea leaves (variety, origin, growing conditions,
etc.) (70). The preparation of fresh green tea cannot totally
extract catechin from the leaves; therefore, the concentration
found differs from the absolute values determined through the
complete extraction of leaves (71). Moreover, catechins are
relatively unstable and could be quantitatively and qualitatively modified during the time frame of the experiment
(72,73). Thus, comparison of ingested doses for animal studies
is not possible because the catechin quantification before
administration is often not known. Moreover, because drinking water or food consumption is not generally indicated, the
ingested quantity per animal cannot be precisely evaluated
(mg/kg metabolic wt). In consequence, the strict relation
between biological effect (effect/dose) and green tea ingestion
is difficult to evaluate between studies.
Generally, studies using animal models show that green tea
(catechins) provide some protection against degenerative diseases. Green tea catechins could act as antitumorigenic agents
and as immune modulators in immunodysfunction caused by
transplanted tumors or by carcinogen treatment. Green tea has
an antiproliferative activity on hepatoma cells and a hypolipidemic activity in hepatoma-treated rats, prevented hepatoxicity in some studies, and could act as a preventive agent
against mammary cancer postinitiation. Long-term feeding of
tea catechins could be beneficial in suppressing high-fat diet
induced obesity by modulating lipid metabolism, could have a

Downloaded from jn.nutrition.org by guest on December 6, 2014

GTE (20 mg/

kg)

3437S

SUPPLEMENT

3438S

TABLE 3
Effects of green tea catechins on other diseases in animal models
EGCg
equivalent Species

GTE (5%)

32.1% of
GTE

Rat

91

10

GTE (5%,
wt:wt)

32.1% of
GTE

Rat

56

GTE (1%,
wt:v)

Rat

42

GTE (2%,
wt:v)

Rat

49

GTE (0.5%,
wt:v)

Rat

28

Green tea
(2%, v:v)

Rat

42

Green tea
(2%, wt:
v)
GTE (5%,
wt:v)

Rat

42

Stress

2-amino-3methylamidazoquinone

Rat

Period Subjects/
d
group

28

beneficial effect against lipid and glucose metabolism disorders

implicated in type 2 diabetes, and could reduce the risk of
cardiovascular disease.
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Biomarkers affected
1 Thyroid weight
2 Body weight
Hypertrophy and/or hyperplasia of
thyroid cells
2 Body weight
1 Thyroid weight
2 Prostate gland weight
2 Testis weight
1 Plasma thyroid stimulating hormone
2 Plasma thyroxine
2 Plasma triiodothyronine
1 Plasma luteinizing hormone

Biomarkers not
affected

Reference
58

Follicle-stimulating
hormone

59

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copper, zinc,
and manganese
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absorption of
2 Calcium absorption
copper
2 Cerebrum calcium content
Copper
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2 Apparent absorption of zinc
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CYP 2E, 2D and
1 Glutathione-S-transferase
3A activity
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Plasma
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1 CYP 1A2 activity
CYP 2E1 activity
1 UDP-GT activity
CYP 3A4 activity
Glutathione Stransferase
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Plasma GSH
concentration
Plasma cysteine
concentration
Plasma
cholesterol
concentration
HDL cholesterol
concentration
Plasma
triglycerides
concentration
Plasma
testosterone
concentration
1 2-amino-3-methylamidazoquinone
urinary excretion

60

1
2
1
1

Liver catalase activity

Liver cytosolic protein
Glutathione S-transferase activity
UDP-GT activity

Epoxide hydrolase
activity

61

62

63

64
65

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3439S

3440S

SUPPLEMENT

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