Molecules: Green Tea (Camellia Sinensis) : A Review of Its Phytochemistry, Pharmacology, and Toxicology

molecules
Review
Green Tea (Camellia sinensis): A Review of Its Phytochemistry,
Pharmacology, and Toxicology
Tiantian Zhao 1 , Chao Li 2 , Shuai Wang 1 and Xinqiang Song 1, *
1 School of Medicine, Xinyang Normal University, Xinyang 464000, China; ttzhao2020@163.com (T.Z.);
ws20095072016@163.com (S.W.)
2 College of Chemistry and Chemical Engineering, Xinyang Normal University, Xinyang 464000, China;
lichaoxynu@163.com
* Correspondence: xqsong@xynu.edu.cn; Tel.: +86-0376-6392267
Abstract: Objectives Green tea (Camellia sinensis) is a kind of unfermented tea that retains the natural
substance in fresh leaves to a great extent. It is regarded as the second most popular drink in the
world besides water. In this paper, the phytochemistry, pharmacology, and toxicology of green tea
are reviewed systematically and comprehensively. Key findings Green tea has been demonstrated to
be good for human health. Nowadays, multiple pharmacologically active components have been
isolated and identified from green tea, including tea polyphenols, alkaloids, amino acids, polysac-
charides, and volatile components. Recent studies have demonstrated that green tea shows versatile
pharmacological activities, such as antioxidant, anticancer, hypoglycemic, antibacterial, antiviral, and
neuroprotective. Studies on the toxic effects of green tea extract and its main ingredients have also
raised concerns including hepatotoxicity and DNA damage. Summary Green tea can be used to assist
the treatment of diabetes, Alzheimer’s disease, oral cancer, and dermatitis. Consequently, green tea
has shown promising practical prospects in health care and disease prevention.
Keywords: green tea; unfermented tea; phytochemistry; pharmacology; toxicology; human health
Citation: Zhao, T.; Li, C.; Wang, S.;
Song, X. Green Tea (Camellia sinensis):
A Review of Its Phytochemistry,
Pharmacology, and Toxicology. 1. Introduction
Molecules 2022, 27, 3909. https://
Tea has a long history, which originates from China and spreads all over the world by
doi.org/10.3390/molecules27123909
direct or indirect ways. Nowadays, tea has been consumed by 3 billion people worldwide,
Academic Editors: Ki Hyun Kim, which is considered as one of the most popular non-alcoholic beverages [1]. Tea can be
Mostafa Rateb and Hossam Hassan classified in many types according to the diverse definition methods in different countries.
Received: 6 May 2022
In China, according to the degree of fermentation, tea is divided into six major tea lines:
Accepted: 13 June 2022
green tea, black tea, white tea, yellow tea, Oolong tea, and dark tea [2]. Green tea was the
Published: 18 June 2022
first tea to be discovered, and it is a non-fermented tea. Green tea retains more natural
substances in fresh leaves and has less vitamin loss, thus forming the characteristics of
Publisher’s Note: MDPI stays neutral
green tea as “clear soup with green leaves and strong flavor convergence”. The main
with regard to jurisdictional claims in
varieties of green tea are Longjing, Biluochun, Huangshanmaofeng, Xinyangmaojian, etc.
published maps and institutional affil-
A large number of researchers have confirmed that green tea possesses chemical
iations.
ingredients that are closely related to human health. Tea polyphenols, caffeine, theanine,
tea polysaccharides, and other components which are extracted and separated from green
tea have pharmacological activities such as anti-cancer [3], anti-oxidation [4], protecting
Copyright: © 2022 by the authors.
the nervous system [5], and lowering blood sugar [6]. Green tea has been considered
Licensee MDPI, Basel, Switzerland. to be suitable for patients with hypertension, hyperlipidemia, coronary heart disease,
This article is an open access article arteriosclerosis, and diabetes. However, it is important to keep in mind that “natural” does
distributed under the terms and not mean perfectly safe. Although the toxic side effects of green tea are relatively small, it
conditions of the Creative Commons must be used with caution in pregnancy, children, and the elderly population.
Attribution (CC BY) license (https:// Tea polyphenols are one of the main components in the formation of the color and
creativecommons.org/licenses/by/ flavor of tea soup and are also important ingredients for tea with health functions [7]. The
4.0/). species, processing method, and fermentation degree are the key factors that affect the
Molecules 2022, 27, 3909. https://doi.org/10.3390/molecules27123909 https://www.mdpi.com/journal/molecules

Molecules 2022, 27, 3909 2 of 23
content of tea polyphenols in tea [8]. Gao et al. analyzed the content of 16 common tea
leaves and found that the content of tea polyphenols in green tea was the highest [9]. They
suggested that green tea was the preferred tea source for the development of tea polyphenol
functional foods [9].
In recent years, numerous domestic and foreign studies are focused on the chemical
composition and pharmacological effects of green tea. At present, there is a lack of sys-
tematic and comprehensive review on the research results of green tea. In this paper, we
review the phytochemistry, pharmacological activity, and toxicology of green tea, with the
purpose of promoting further research on green tea and developing the precious green tea
resources in China.
2. Methods
The data were collected by searching PubMed, Google Scholar, Web of Science, and
CNKI. The keywords used as search terms were green tea, phytochemical, chemical compo-
sition, EGCG, pharmacology, tea polyphenols, antioxidant, cancer, diabetes, antibacterial,
antiviral, AD, PD, immune T cells, and toxicology. Various related articles and websites
were also included. For further research, the references of some selected articles were also
searched. The inclusion criteria for this review were systematic reviews and experimental
studies on green tea. However, studies on other types of tea such as yellow tea, dark tea,
or other natural plants were considered ineligible for inclusion. In addition, other types
of articles, such as conference reports, case reports, and short communications, were also
excluded. No time limitation was considered in this review.
3. Phytochemistry
Tea is rich in healthcare ingredients and pharmacologically active ingredients. From
the beginning of the 19th century to the present, it has been reported that more than
500 chemical components have been isolated from tea, including more than 400 organic
compounds and more than 40 inorganic compounds [10]. Green tea, as a non-fermented
tea, retains the original chemical components of tea completely. This section details the
research on green tea in phytochemistry and classifies the main compounds in green tea.
The chemical structures of the main compounds that have been identified are listed in the
figures below.
3.1. Tea Polyphenols

Tea polyphenols is a general term for polyphenols in tea. There are about 30 kinds
of compounds, mainly composed of catechins, flavonoids, anthocyanins, and phenolic
acids [11]. The highest content of tea polyphenols in green tea is 20–30%, which can be
used as an excellent natural antioxidant.
3.1.1. Catechins (1–5)

The catechins in tea mainly include catechin (C), epicatechin (EC), epigallocatechin
(EGC), epicatechin gallate (ECG), and epigallocatechin Gallate (EGCG) [12]. As shown
in Figure 1. A large number of studies have shown that catechins in green tea, especially
EGCG, have anti-cancer [13], anti-viral [14], and anti-oxidant effects [4].
3.1.2. Flavonoids (6–25)

Green tea is rich in flavonol glycosides, mainly including myricetin glycosides, quercetin
glycosides, and behenyl glycosides [15,16]. This sugar chain consists of monosaccha-
rides, such as glucose, galactose, rhamnose, arabinose, etc., and disaccharides or trisaccha-
rides [17], as shown in Figure 2.
Anthocyanins are a class of water-soluble pigments and belong to flavonoids [18]. The
content of anthocyanins is not high in tea, but due to its obvious bitter taste, it has a great
impact on tea quality [19]. As presented in Figure 3.
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(+)−Cateehin (C) (−)−Epicatechin (EC) (−)−Epigallocatechin (EGC)
(+)−Cateehin (C) (−)−Epicatechin (EC) (−)−Epigallocatechin (EGC)
(−)−Epicatechin gallate (ECG) (−)−Epigallocatechin gallate (EGCG)

Figure 1. Chemical structures of catechins isolated from green tea.

Green tea is rich in flavonol glycosides, mainly including myricetin glycosides, quer-
cetin glycosides, and behenyl glycosides [15,16]. This sugar chain consists of monosaccha-
rides, such as glucose, galactose, rhamnose, arabinose, etc., and disaccharides or trisac-
charides [17], as shown in Figure 2.
Anthocyanins are a class of water-soluble pigments and belong to flavonoids [18].
(−)−Epicatechin gallate (ECG)of anthocyanins is not high (−)−Epigallocatechin
The content gallate (EGCG)
in tea, but due to its obvious bitter taste, it has a
great
Figure impact
1. on
Chemical tea quality
structures of [19]. As presented
catechins isolated in
from Figure
green 3.
tea.
Figure 1. Chemical structures of catechins isolated from green tea.

Green tea is rich in flavonol glycosides, mainly including myricetin glycosides, quer-
cetin glycosides, and behenyl glycosides [15,16]. This sugar chain consists of monosaccha-
rides, such as glucose, galactose, rhamnose, arabinose, etc., and disaccharides or trisac-
charides [17], as shown in Figure 2.
Anthocyanins are a class of water-soluble pigments and belong to flavonoids [18].
The content of anthocyanins is not high in tea, but due to its obvious bitter taste, it has a
6 Myricetin-3-rhamnosylglucoside R1 = OH R2 = OH R3 = OH R4 = H R5 = X2
great impact on tea quality [19]. As presented in Figure 3.
7 Myricetin-3-galactoside R1 = OH R2 = OH R3 = H R4 = OH R5 = X1
8 Myricetin-3-glucoside R1 = OH R2 = OH R3 = OH R4 = H R5 = X1
9 Quercetin-3-glucosyl-rhamnosyl-galactoside R1 = H R2 = OH R3 = H R4 = OH R5 = X3
10 Quercetin-3-glucosyl-rhamnosyl-glucoside R1 = H R2 = OH R3 = OH R4 = H R5 = X3
11 Quercetin-3-rhamnosylgalactoside R1 = H R2 = OH R3 = H R4 = OH R5 = X2
12 Quercetin-3-rhamnosylglucoside R1 = H R2 = OH R3 = OH R4 = H R5 = X2
13 Quercetin-3-galactoside R1 = H R2 = OH R3 = H R4 = OH R5 = X1
14 Quercetin-3-glucoside R1 = H R2 = OH R3 = OH R4 = H R5 = X1
6 15 Kaempferol-3-glucosyl-rhamnosyl-galactoside
Myricetin-3-rhamnosylglucoside R1R=1 OH= H R2R=1 OH
=H R3R=3 =OH
H RR44 == OH
H R55 = X23
7 16 Kaempferol-3-glucosyl-rhamnosyl-glucoside
Myricetin-3-galactoside R = H R
R1 = OH R2 = OH
1 1 = H R 3
3 = OH
H R =
R4 = OH
4 H R55 = X13
8 17 Kaempferol-3-rhamnosylgalactoside
Myricetin-3-glucoside R1R=1 OH= H R2R=1 OH
=H R3R=3 =OH
H RR44 == OH
H R55 == X
R X12
18 Kaempferol-3-rhamnosylglucoside
9 Quercetin-3-glucosyl-rhamnosyl-galactoside R
R1 = H
1 = H R =
R2 = OH
1 H R =
R3 = H
3 OH R =
R4 = OH
4 H R =
R5 = X
5 X32
1019 Quercetin-3-glucosyl-rhamnosyl-glucoside
Kaempferol-3-galactoside RR1 1= =HH R2R=1 OH
=H R3R=3 =OH
H RR44 == OH
H R55 == X
R X31
11 20 Kaempferol-3-glucoside
Quercetin-3-rhamnosylgalactoside R
R1 = H
1 = H R =
R2 = OH
1 H R =
R3 = H
3 OH R =
R4 = OH
4 H R =
R5 = X
5 X21
12 Quercetin-3-rhamnosylglucoside R1 =ofHflavonoids
Figure 2. Chemical structures R2 = OH R3 =green
isolated from OH tea. R4 = H R5 = X2
13 Quercetin-3-galactoside R1 = H R2 = OH R3 = H R4 = OH R5 = X1
14 Quercetin-3-glucoside R1 = H R2 = OH R3 = OH R4 = H R5 = X1
15 Kaempferol-3-glucosyl-rhamnosyl-galactoside R1 = H R1 = H R3 = H R4 = OH R5 = X3
16 Kaempferol-3-glucosyl-rhamnosyl-glucoside R1 = H R1 = H R3 = OH R4 = H R5 = X3
17 Kaempferol-3-rhamnosylgalactoside R1 = H R1 = H R3 = H R4 = OH R5 = X2
18 Kaempferol-3-rhamnosylglucoside R1 = H R1 = H R3 = OH R4 = H R5 = X2
19 Kaempferol-3-galactoside R1 = H R1 = H R3 = H R4 = OH R5 = X1
20 Kaempferol-3-glucoside R1 = H R1 = H R3 = OH R4 = H R5 = X1
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Figure
Figure 2.
2. Chemical
Chemical structures
structures of
of flavonoids
flavonoids isolated
isolated from
from green
green tea.
tea.
21
21 Cyanidin
Cyanidin R11 == OH
R OH R
R22 == OH
OH RR33 == H
H R
R44 == OH
OH R
R55 == OH
OH R
R66 == H
H R
R77 == OH
OH
22
22 Delphindin R
Delphindin R11 == OH OH R
R22== OH
OH R
R33== OH OH R
R44== OH
OH R
R55== OH
OH R
R66== HH R
R77== OH
OH
23
23 Pelargonidin
Pelargonidin R R11== H
H R
R22== OH
OH RR33== HH R
R44== OH
OH R
R55== OH
OH R
R66== HH R
R77== OH
OH
24
24 Malvidin
Malvidin R = OCH
R1 = OCH33
1 R =
R2 = OH
2 OH R = OCH
R3 = OCH33
3 R =
R4 = OH
4 OH R =
R5 = OH
5 OH R =
R6 = H
6 H R =
R7 = OH
7 OH
25
25 Petunidin
Petunidin R
R11== OHOH R
R22== OH
OH R
R33== OCH
OCH33 R
R44== OH
OH R
R55== OH
OH R
R66== HH R
R77== OH
OH
Figure
Figure 3.
Figure Chemical
3.3.
Chemical structures
structures
Chemical of anthocyanins
ofof
structures anthocyanins isolated
isolated
anthocyanins from
from
isolated green
from greentea.
green tea.
tea.
3.1.3.
3.1.3.
3.1.3. Phenolic
Phenolic
Phenolic Acids
Acids
Acids (26–31)
(26–31)
(26–31)
AtAtAtpresent,
present,there
present, thereare
there arefew
are fewstudies
few studies on
studies on phenolic
on phenolic
phenolic acid
acidcompounds
compoundsin
compounds ingreen
in greentea.
green tea.The
tea. Thecontent
The con-
con-
tent of phenolic acids in green tea is relatively small, but it includes various ingredientsas
of
tent phenolic
of phenolicacids in
acids green
in tea
green is relatively
tea is small,
relatively but
small, it includes
but it various
includes ingredients
various such
ingredients
gallic
such
such as acid,
as gallicchlorogenic
gallic acid, acid, caffeic
acid, chlorogenic
chlorogenic acid, acid, p-coumaric
acid, caffeic
caffeic acid, acid, ellagic
acid, p-coumaric
p-coumaric acid, acid, quinic
acid, ellagic
ellagic acid, acid, and
acid, quinic
quinic tea
acid,
acid,
gallate
and
and tea [20].
tea gallate As presented
gallate [20].
[20]. As in Figure
As presented
presented in 4.
in Figure
Figure 4.
4.
Gallic
Gallic acid
acid Chlorogenic
Chlorogenic acid
acid Caffeic
Caffeic acid
acid
p-Coumaric
p-Coumaric acid
acid Ellagic
Ellagic acid
acid Quinic
Quinic acid
acid
Figure
Figure 4.
Figure Chemical
4.4.
Chemical structures
structures
Chemical of phenolic
ofof
structures phenolic acids
acids
phenolic isolated
isolated
acids from
from
isolated green
from greentea.
green tea.
tea.
3.2.
3.2.
3.2. Alkaloids
Alkaloids
Alkaloids (32–34)
(32–34)
(32–34)
The
TheThe alkaloids
alkaloids
alkaloids inin
in teatea
tea areare
are mainly
mainly
mainly purine
purine
purine alkaloids.
alkaloids.
alkaloids. Among
Among
Among them,
them,
them, thethe
the caffeine
caffeine
caffeine content
content
content is
is
is
the the
most most (2~5%).
(2~5%). Secondly,
Secondly, it it
also also contains
contains a a
smallsmall
amountamount
of of theophylline
theophylline
the most (2~5%). Secondly, it also contains a small amount of theophylline and theobro- and and
theobro-theo-
bromine
mine
mine [21]. [21].
TheseThese
[21]. These threethree
three alkaloids
alkaloids
alkaloids are
are thearemain
the the main
main material
material
material basisbasis
basis for
for theforrefreshing
the the refreshing
refreshing effecteffect
effect of teaof
of tea
tea
[22]. [22]. The names and structures of these three alkaloids are detailed in Figure 5.
[22]. The
The names
names andand structures
structures of of these
these three
three alkaloids
alkaloids are
are detailed
detailed in in Figure
Figure 5.
5.
3.3. Amino Acids (35–39)
The type and content of amino acids in tea is one of the most important substances
affecting tea quality. Tea contains about 1% to 4% of amino acids. So far, 26 amino acids
have been found in tea, including 20 protein amino acids and 6 non-protein amino acids.
The highest content is theanine, glutamic acid, arginine, serine, and aspartic acid, shown in
Figure 6 [23]. Theanine and γ-aminobutyric acid are two important active amino acids in
tea. They have notable protective effects on the nervous system [24,25]. Theanine accounts
Molecules 2022, 27, 3909 5 of 23
Caffeine Theophylline Theobromine

for approximately 50% of all amino acids; however, γ-aminobutyric acid is low. Chen et al.
Figure 5. Chemical structures of alkaloids isolated from green tea.
used an amino acid analyzer to determine the content of free amino acids in several different
Molecules 2022, 27, x FOR PEER REVIEW 5 of 23
teasAmino
3.3. and found
Acids that there was no significant difference in the amino acid composition of
(35–39)
green tea and black tea [26].
The highest content is theanine, glutamic acid, arginine, serine, and aspartic acid, shown
in Figure 6 [23]. Theanine and γ-aminobutyric acid are two important active amino acids
in tea. They have notable protective effects on the nervous system [24,25]. Theanine ac-
counts for approximately 50% of all amino acids; however, γ-aminobutyric acid is low.
Chen et al. used an amino acid analyzer to determine the content of free amino acids in
Caffeine several different teas andTheophylline Theobromine
found that there was no significant difference in the amino acid
composition
Figure 5. of green
Chemical tea and
structures black
of tea
alkaloids [26].
isolated from green tea.
Figure 5. Chemical structures of alkaloids isolated from green tea.
3.3. Amino Acids (35–39)

The highest content is theanine, glutamic acid, arginine, serine, and aspartic acid, shown
in Figure 6 [23]. Theanine and γ-aminobutyric acid are two important active amino acids
in tea. They have notable protective effects on the nervous system [24,25]. Theanine ac-
L-Theanine counts for approximately 50% acid
Glutamic of all amino acids; however, γ-aminobutyric
Arginine acid is low.
Chen et al. used an amino acid analyzer to determine the content of free amino acids in
several different teas and found that there was no significant difference in the amino acid
composition of green tea and black tea [26].
Serine Aspartic acid

Figure
Figure6.6.Chemical
Chemicalstructures
structuresof
ofamino
aminoacids
acidsisolated
isolatedfrom
from green
green tea.
tea.
3.4.Carbohydrate
3.4. Carbohydrate
L-Theanine Glutamic acid Arginine
Thereason
The reasonwhy
whythethetea
tea soup
soup is
is slightly
slightlysweet
sweetisis that
that tea
tea contains
containsaa small
small amount
amountof of
monosaccharides and disaccharides, such as glucose, fructose, galactose,
monosaccharides and disaccharides, such as glucose, fructose, galactose, sucrose, etc.sucrose, etc. Most
carbohydrates
Most in teainare
carbohydrates teapolysaccharides,
are polysaccharides,suchsuch
as cellulose,
as cellulose,starch, andand
starch, pectin, which
pectin, are
which
insoluble in water [11].
are insoluble in water [11].
3.5. Aromatic Ingredients (40–56)
The substances that form the aroma of green tea are mainly volatile aromatic sub-
stances. Among the chemical components of green tea, the aroma components do not
stances. Among the chemical components of green tea, the aroma components do not oc-
Serine occupy much content, about Aspartic acid to 0.020%, but the types are quite complicated [27].
0.005%
cupy much content, about 0.005% to 0.020%, but the types are quite complicated [27].
There have
Figurehave been many
6. Chemical reports
structures on the analysis
of amino of volatile components in green tea, and at
There been many reports on theacids isolated
analysis from green
of volatile tea.
components in green tea, and at
the same time, new components have been discovered and identified. The main aroma
components of green tea are listed in Figure 7.
3.4. Carbohydrate
The reason
3.6. Organic Acidswhy the tea soup is slightly sweet is that tea contains a small amount of
(57–65)
monosaccharides and disaccharides, such as glucose, fructose, galactose, sucrose, etc.
Organic acids in green tea, as a water-soluble substance, are one of the main compo-
Most carbohydrates in tea are polysaccharides, such as cellulose, starch, and pectin, which
nents that affect the aroma and taste of tea soup [28,29]. More than 40 organic acids have
are insoluble
been in water
isolated and [11]. from tea, including free organic acids in tea soup and more
identified
than 30 in aroma components [30]. Volatile compounds such as acetic acid, butyric acid,
stances. Among the chemical components of green tea, the aroma components do not oc-
cupy much content, about 0.005% to 0.020%, but the types are quite complicated [27].
There have been many reports on the analysis of volatile components in green tea, and at
Molecules 2022, 27, 3909 6 of 23
and hexenoic acid are classified under the aromatic substance category. Therefore, this
section only describes the non-volatile organic acids in Figure 8.
3.7. Mineral Elements

Molecules 2022, 27, x FOR PEER REVIEW The inorganic compounds in tea are called ash, which is mainly composed of6some of 23
mineral elements and their oxides. Ash content is one of the indexes for quality inspection
of tea export. The most abundant mineral elements are P and K, followed by Ca, Mg,
Fe, Mn, Al, S, Si, and trace elements such as Zn, Cu, and F [31–33]. Due to the valuable
the same time, new components have been discovered and identified. The main aroma
significance of mineral elements on the physiological function of tea plant and human body,
components of green tea are listed in Figure 7.
it has aroused extensive attention of scientists.
Dimethyl sulfide Pentanal 8-Octadecenoic acid methyl ester
Dibutyl phthalate Hexanal Acetone
Hexadecane 1-Pentanol
Heptanal 2-methylbutyraldehyde 3-Methylbutyraldehyde
Heptadecane
Methyl hexadecanoate Acetic acid
1-Ethylpyrrole 2-Methylpropionaldehyde Naphthalene

Figure 7. Chemical
Figure 7. Chemical structures of aromatic
structures of aromatic ingredients
ingredients isolated
isolated from
from green
green tea.
tea.
3.6. Organic Acids (57–65)

Organic acids in green tea, as a water-soluble substance, are one of the main compo-
nents that affect the aroma and taste of tea soup [28,29]. More than 40 organic acids have
been isolated and identified from tea, including free organic acids in tea soup and more
than 30 in aroma components [30]. Volatile compounds such as acetic acid, butyric acid,
and hexenoic acid are classified under the aromatic substance category. Therefore, this
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7 of
Oxalic acid Tartaric acid Formic acid L-malic acid
Ascorbic acid Lactic acid Citric acid
Succinic acid Fumaric acid

Figure 8.8.Chemical
Figure Chemicalstructures
structuresofoforganic
organicacids
acidsisolated
isolatedfrom
fromgreen
greentea.
tea.
3.8.Mineral
3.7. OthersElements
In addition
The inorganictocompounds
the chemicalin components
tea are calledmentioned
ash, whichabove, green
is mainly tea also contains
composed of some a
certain amount of vitamins, such as vitamin B, vitamin C, and vitamin E [34]; enzymes,
mineral elements and their oxides. Ash content is one of the indexes for quality inspection
such as glucosidases and lipoxidases [35]; and chlorophyll, which is a highly
of tea export. The most abundant mineral elements are P and K, followed by Ca, Mg, safe natural
Fe,
edible pigment [36].
Mn, Al, S, Si, and trace elements such as Zn, Cu, and F [31–33]. Due to the valuable signif-
icance of mineral elements on the physiological function of tea plant and human body, it
4. Pharmacology
has aroused extensive attention of scientists.
4.1. Antioxidant Effects
As early as 1997, it was reported that green tea extract and its three main compo-
3.8. Others
nents, including tea polyphenols, theanine, and caffeine, have the ability to effectively
In addition to the chemical components mentioned above, green tea also contains a
inhibit copper-catalyzed low-density lipoprotein (LDL) lipid peroxidation. Moreover,
certain amount of vitamins, such as vitamin B, vitamin C, and vitamin E [34]; enzymes,
Yokozawa T et al. found that the antioxidant activity of green tea extract was in a dose-
such as glucosidases and lipoxidases [35]; and chlorophyll, which is a highly safe natural
dependent manner, and the antioxidant activity of the three components was tea polyphe-
edible pigment [36].
nols > theanine > caffeine. Finally, they came to the conclusion that chelated metal ion
copper is considered to be one of the possible mechanisms of green tea against peroxi-
4. Pharmacology
dation [37]. In the current study, the antioxidant activity of green tea could be studied
4.1.
byAntioxidant
two different Effects
chemical tests. (1) DPPH free radical scavenging test. Sun et al. (2007)
demonstrated
As early as that 1997,the anti-free
it was radical
reported ability
that greenoftea
antioxidant
extract and compounds
its three maincontained in green
components,
tea was ranked
including as EGCG > theanine,
tea polyphenols, ECG > EGC and> caffeine,
EC. In 2020,
haveonethe
study showed
ability that the ethanolic
to effectively inhibit
extract of green tea
copper-catalyzed has powerful
low-density antioxidant
lipoprotein activity
(LDL) lipid by DPPH testing
peroxidation. with lowYokozawa
Moreover, IC50 values
T of
et0.005 µg/mL
al. found that[38].
the(2) Total oxy-radical
antioxidant activityscavenging
of green tea capacity
extract(TOSC)
was inassay [39]. Kang et al.
a dose-dependent
(2010) revealed
manner, and the that ECG andactivity
antioxidant EGCG of have
thebeen
threeproven to havewas
components the greatest antioxidant
tea polyphenols >
effects, followed by EC, C, GA, and EGC [40]. In summary, the
theanine > caffeine. Finally, they came to the conclusion that chelated metal ion copperresults of the two test
is
methods were
considered to beconsistent.
one of the possible mechanisms of green tea against peroxidation [37]. In
In recent
the current study, years, there is noactivity
the antioxidant doubt that the antioxidant
of green tea could beeffects
studiedofby tea
twopolyphenols
different
and catechins
chemical tests. (1)in DPPH
green teafreehave been
radical extensively
scavenging studied
test. Sun etbyal.scholars all over the world.
(2007) demonstrated that
However, little research has been performed on antioxidants in green
the anti-free radical ability of antioxidant compounds contained in green tea was ranked tea polysaccharides.
asWang
EGCG et >al.ECG
(2012) reported
> EGC > EC.that tea leaves
In 2020, polysaccharides
one study showed that(TLPS), tea seedextract
the ethanolic polysaccharides
of green
(TSPS), and tea flower polysaccharides (TFPS) isolated from tea
tea has powerful antioxidant activity by DPPH testing with low IC50 values of 0.005 leaves, flowers, and seeds,
μg/mL
Molecules 2022, 27, 3909 8 of 23
at concentrations ranging from 0.5~100 µg/mL, could exhibit a dose-dependent superoxide

scavenging activity. In particular, at a concentration of 400 µg/mL, the superoxide radical
scavenging rates of TLPS, TFPS and TSPS were as high as 90.45%, 78.58%, and 58.34%,
respectively [41].
In addition to this, Hsu et al. (2014) suggested that the green tea extract (125, 625, and
1250 mg/kg, i.g., for four weeks) showed notable protective effects on redox imbalance in
the brain of aging mice, and this mechanism may be associated with more efficient clearance
of ROS by increasing the activity of antioxidant enzymes, such as superoxide dismutase
(SOD), catalase, glutathione peroxidase (GSH-Px), and Glutathione reductase (GSH-Rd) in
the brain [42]. In one report of 2018, it was reported that the antioxidant activity of green
tea extract could protect against hepatotoxicity caused by excess acetaminophen (APAP) in
mice [43].
4.2. Anticancer Effects

It is reported that green tea has a therapeutic effect on various cancer types [44,45]. In
recent years, research on the anticancer mechanism of green tea has attracted more and
more attention. It is mainly reflected in the following points.
(1) Inhibiting migration and invasion of tumor cells. In 2012, an interesting experiment
showed that EGCG inhibited the growth of HeLa cells in a dose- and time-dependent
manner. In particular, the IC50 values of cell viability of HeLa cells at concentrations of
50 µM and 100 µM were 57.2% and 29.3% at 48 h, respectively. In addition, Sharma et al.
revealed that this mechanism may be that EGCG could effectively inhibit the invasion
and migration of HeLa cells and regulate the expression of MMP-9 and TIMP-1 [46].
Luo et al. (2014) reported for the first time that green tea extract possessed an ability to
significantly inhibit lung and liver metastasis in BALB/c mice with 4T1 tumors with
reduced abilities of 54.5% and 72.6%, respectively [47].
(2) Inducing apoptosis. Cerezo-Guisado et al. (2015) performed cytotoxic activity tests
on EGCG, a major component of green tea. The results showed that the mortality of
HT-29 cells could reach 100% after treatment with 100 or 200 µM EGCG. In addition,
they revealed that EGCG could induce apoptosis in colon cancer cells by modulating
Akt, ERK1/2 and p38 MAPK signaling pathways [48]. Roychoudhury et al. (2018)
treated pig ovarian granulosa cells with five different doses of green tea extract, and
evaluated the hormone released by granulosa cells by EIA. It was found that at the
highest dose (200 µg/mL), the apoptosis markers caspase-3 and p53 were increased in
granulosa cells. Therefore, they suggested that activation of caspase-3 and p53 could
ultimately induce apoptosis in ovarian cells [49].
(3) Inhibiting tumor cell angiogenesis. In vitro, EGCG displayed growth inhibition on
HuH7 cells and Hc cells with IC50 values of 25 µg/mL and 84 µg/mL, respectively.
Further investigations revealed that the mechanism of these effects may be associ-
ated with the inhibition of VEGF binding to receptor tyrosine kinases and decreased
expression of Bcl-xL protein and VEGF mRNA [50].
(4) Inhibiting the proliferation of tumor cells. Studies have found that EGCG could
inhibit the growth of androgen-sensitive human prostate cancer cells (PCA) in a dose-
dependent manner, and this effect may be mediated by G0 /G1 phase cell cycle arrest
caused by WAF1/p21 [51]. Ma et al. (2013) reported that EGCG could effectively
inhibit the growth of gastric cancer cell line NCI-N87 in a time- and dose-dependent
manner. At the same time, they found that the new mechanism in the treatment of
gastric cancer could be that EGCG could increase the expression of KLF4, change
the expression of p21, CDK4 and cyclin D1, and then arrest the cell cycle in G0 /G1
phase [52].
(5) Other mechanisms. 4-NQO has been confirmed to induce a variety of cancers [53]. In
one report of 2008, Srinivasan et al. established a 4-NQO-induced rat oral cancer model
to study the therapeutic effect of green tea polyphenols on oral cancer. After treatment
with 200 mg/kg of green tea polyphenols, the number of tumors, tumor volume, and
Molecules 2022, 27, 3909 9 of 23
oral squamous cell carcinoma were significantly decreased by 66.27%, 56.80%, and
88.75%, respectively. In addition, they also suggested that GTP acted as a detoxifier
here, which in turn inactivated carcinogens [54]. In 2012, Lu et al. revealed that green
tea extract could up-regulate the expression of ANX1, an important anti-inflammatory
mediator [55], in human non-small cell lung cancer cell lines, and down-regulate the
expression of COX-2. Therefore, they proposed that the new mechanism of green tea
extract to prevent lung cancer may be that green tea polyphenols could target a variety
of inflammatory pathways to induce tumor cell apoptosis [56].
4.3. Anti-Diabetic Effects

Anti-diabetic effect is one of the important biological activities of green tea. Current
studies have shown that the anti-diabetic effect of green tea is mainly achieved through the
following four mechanisms.
(1) Improving insulin resistance. The endocrine function of adipocytes plays a central role
in insulin resistance [57]. Wu et al. found that green tea polyphenols could increase
insulin sensitivity in rats by increasing the absorption of glucose by adipocytes and
their ability to bind to insulin [58]. Membrane transport of insulin-regulated glucose
transport protein (GLUT-4) is critical for maintaining blood glucose balance in the
body [59]. Serisier et al. found that green tea extract (80 mg/kg, i.g., for 12 weeks)
could improve insulin sensitivity and lipid distribution by altering the expression of
genes involved in glucose and lipid homeostasis, including GLUT-4, LPL, and PPAR,
which ultimately led to a decrease in blood glucose and an improvement in insulin
resistance in obese dogs [60].
(2) Improving glucose metabolism. Sundaram et al. (2013) revealed that green tea extract
(75 mg/kg, i.g., for 30 days) had significant hypoglycemic effects on streptozotocin-
induced diabetic rats. Moreover, its ability to lower blood sugar was comparable to
the oral hypoglycemic drug metformin. The mechanism of this action was related
to the increase of glycogen content in the liver and the change of the activity of key
enzymes in glucose metabolism [61].
(3) Promoting insulin secretion. Wang et al. isolated the water-soluble polysaccharide
7WA from the leaves of green tea and studied its anti-diabetic effect in 2015. They
found that 7WA could promote insulin secretion and had a significant hypoglycemic
effect through a possible mechanism of cAMP-PKA dependent pathways [62].
(4) Improving diabetic complications. Impaired cardiac function in diabetes is closely
related to hyperglycemia [63,64]. Green tea is rich in polyphenol antioxidants, which
can effectively prevent heart disease [65]. Babu et al. found that green tea extract
(300 mg/kg, i.g., for four weeks) could significantly reduce the blood sugar, lipid
peroxide, the levels of triglyceride, and the degree of protein glycosylation in the heart
of diabetic rats. In 2016, Zhong et al. demonstrated that EGCG treatment with 10 µM
showed significant inhibiting effects on neural tube defects in diabetic pregnant mice
with the defect rate decreased from 29.5% to 2%. The underlying mechanism for this
effect might be related to that 10 µM EGCG could inhibit the hypermethylation of
DNA by blocking the increased expression and activity of DNA methyltransferase in
maternal diabetic mice [66].
4.4. Antibacterial Effects

It is well known that green tea exhibits antibacterial effects against a variety of bacteria.
In 2000, Yee et al. first reported that green tea had the ability to inhibit Helicobacter pylori activity.
Their studies have shown that EGCG, and EC could inhibit the growth of Helicobacter pylori
with MIC90 values of 50~100 µg/mL, and 800~1600 µg/mL, respectively. The results
indicated that EGCG might be the most effective component against Helicobacter pylori
activity [67]. In one report of 2006, Anand et al. found that EGCG could down-regulate
TACO gene expression in a dose-dependent manner by flow cytometry experiments to
inhibit the survival of Mycobacterium tuberculosis in macrophages. Moreover, they also
Molecules 2022, 27, 3909 10 of 23
proposed that EGCG has the potential to be an effective drug for the treatment of tuberculo-
sis [68]. As early as 1995, some scholars have found that green tea extract could effectively
inhibit the growth of major foodborne pathogens, including E. coli, Staphylococcus aureus,
Salmonella typhimurium, Listeria monocytogenes, and so on [69]. However, it is unclear what
the main antibacterial ingredients in green tea extracts are, and which bacteria are most
strongly inhibited. In 2006, Si et al. used HSCCC technology to isolate epicatechin gallate
(ECG), epigallocatechin gallate (EGCG), epicatechin (EC) and caffeine (CN) from green tea
extracts and further compared their antibacterial activity. Then, it was found that EGCG
had the highest antibacterial activity, especially the most significant inhibitory effect on
S. aureus with the MIC90 value of 58 mg/L [70]. Moreover, Sharma et al. (2012) revealed
that green tea extracts showed significant antibacterial activity against skin pathogens
in vitro, and this mechanism was mainly related to preventing bacterial adhesion [71].
Some studies have shown that drinking green tea was beneficial to oral health [72,73].
Moreover, Fournier-Larente J et al. further studied the effect of green tea on periodontal
pathogens. In vitro, both green tea extract and EGCG exhibited significant antibacterial
effects on Porphyromonas gingivalis with MIC values ranging from 250 to 1000 mg/mL,
125 to 500 mg/mL, respectively. This mechanism for effect was related to reducing the
adhesion to P. gingivalis and regulating the gene expression of P. gingivalis [74]. These
findings showed that green tea could be regarded as a natural treatment for periodontitis.
In 2019, Ignasimuthu K et al. revealed that the inhibitory effect of green tea on common
food-borne pathogens was enhanced by increasing its lipophilicity [75].
4.5. Antiviral Effects

In 2002, it was reported that when the concentration of EGCG was greater than 1 µM,
EGCG destroyed virus particles and significantly inhibited post-adsorption entry and
reverse transcription in acutely infected monocytes. In addition, above 10 µM, protease
kinetics was also inhibited. At the same time, they found that the inhibitory effect of EGCG
modified by liposomes was significantly improved [76]. In addition, it has been reported
that catechin in green tea could reversibly inhibit HIV-1 integrase activity [77]. In 1993,
there were studies have shown that EGCG could affect the infectious capacity of influenza
viruses by agglutinating the virus [78]. Song et al. (2005) found that the order of antiviral
activity of green tea polyphenols was EGCG > ECG > EGC. Among them, EGCG had the
strongest activity, and its EC50 value for influenza A virus was 22~28 µM [79]. The World
Health Organization (WHO) considers hepatitis B to be the world’s most important public
health problem. Xu et al. (2008) revealed that green tea extract (GTE) could significantly
inhibit the production of hepatitis B virus (HBV), and pointed out that the efficacy of EGCG
was relatively weak compared with GTE. However, the exact mechanism of GTE anti-HBV
needs to be further elucidated [80].
Apart from these, foodborne viruses, such as the human Novo virus (Nov) and
hepatitis A virus (HAV), are considered to be the major pathogens of food-borne diseases.
Randazzo W et al. suggested that green tea extract (10 mg/mL, for 30 min) could cause
MNV and HAV to be completely inactivated in the surface disinfection test. The results
showed that green tea extract could be used as a natural disinfectant to improve food safety
and quality [81]. Zika virus (ZIKV), transmitted by mosquito bites, could cause a variety
of neurological diseases [82]. Sharma et al. (2017) initially explained that this potential
mechanism by which EGCG inhibited ZIKV entry into host cells might be related to the
binding of envelope proteins [83].
Since the rapid spread of Corona Virus Disease 2019 (COVID-19), due to the shortage of
antiviral medicines, finding alternative medicines from natural herbs to prevent COVID-19
is considered a safe strategy to prevent the pandemic. Mhatre S et al. reported and
summarized the research of EGCG in anti-COVID-19 virus in detail, and then proposed
that EGCG can be used as a dietary supplement or functional food for the prevention
and treatment of COVID-19 [84]. Whether EGCG has a synergistic effect on a COVID-19
Molecules 2022, 27, 3909 11 of 23
vaccine is the focus of future research by discussing the multiple antiviral inhibitory effects
of EGCG [85].
4.6. Neuroprotective Effects

Green tea is rich in polyphenols [86]. The brain permeability of polyphenols makes
it an important class of drugs for the treatment of neurodegenerative diseases. There are
studies have shown that green tea polyphenols play an important role in the treatment of
neurodegenerative diseases. The protective effect on the nervous system is mainly reflected
in the following aspects.
(1) Effect on Alzheimer’s disease (AD). Alzheimer’s disease is characterized by memory
and other cognitive declines. In 2008, Kaur et al. showed that green tea extract (0.5%,
i.g., for 8 weeks) could significantly improve learning and memory in aged rats, and
they also found that green tea extract had selective inhibition of acetylcholinesterase.
It was reported that green tea catechins could promote cognitive dysfunction in AD
model rats through the antioxidant defense, but the exact defense mechanism still
needs to be further explored [87]. In one report of 2018, L-theanine could improve
memory and hippocampal LTP in AD mice. This effect may be related to the regu-
lation of hippocampal synaptic efficacy through the dopamine D1/5-PKA pathway.
Moreover, they proposed a point that L-theanine could be a candidate drug for AD
treatment [88]. An interesting study has shown that green tea had better neuroprotec-
tive effects than black tea on memory deficit and hippocampal oxidation status in AD
mice [89].
(2) Effect on Parkinson’s disease (PD). EGCG, a major active ingredient of green tea
polyphenols, was a natural iron chelator that had a neuroprotective effect on neurotox-
ins in mice and rats [90]. Both NO and reactive oxygen species (NOS) are involved
in the pathogenesis of neurological diseases such as PD [91]. Guo et al. used various
techniques, such as immunohistochemistry, to reveal that green tea polyphenols (GTP)
could protect dopamine neurons in 6-OHDA-treated PD rat models through a pathway
related to inhibition of NO and reactive oxygen species (ROS) [92]. In one recent study,
green tea polyphenols (GTP) possessed an ability to significantly improve nerve redox
imbalance and mitochondrial dysfunction by regulating circadian rhythm [93].
(3) Effect on cerebral ischemia. The overexpression of MMPs is closely related to the
pathological process of focal cerebral ischemia [94]. In 2009, Park et al. suggested that
EGCG at a dose of 50 mg/kg could reduce neuronal damage after cerebral ischemia.
This potential mechanism may be related to the inhibition of MMP-9 activity [95]. In
addition, it has been reported that 400 mg/kg of green tea polyphenols could improve
the spatial cognitive ability after chronic cerebral hypoperfusion by scavenging oxygen
free radicals, reducing the production of lipid peroxides and reducing the damage
of oxidized DNA, thereby playing a neuroprotective role [96]. Theanine is easily
involved in various neurophysiological activities through the blood–brain barrier, and
the neuroprotective effect of theanine on brain damage caused by cerebral ischemia
has recently been reported [97]. In 2020, Zhao et al. studied the exact molecular
mechanism of the protective effect of cerebral ischemia/reperfusion (IR) injury and
found that theanine had a protective effect on hippocampal injury in IR rats. This
mechanism may also be related to inhibition of HO-1 expression and activation of the
ERK1/2 reperfusion injury pathway, in addition to inhibition of oxidative stress [98].
(4) Effect on brain injury. Some pesticides have been confirmed to be an environmental
toxin that causes degeneration of dopaminergic neurons [99]. Tai et al. reported that
EGCG had a protective effect on DDT-induced dopaminergic cell death [100]. It is
well known that heavy metal poisoning, especially lead, can cause nervous system
damage [101]. In addition, 5 µg/L green tea extract had effective protection against
lead-induced brain oxidation and DNA damage in rats [102]. It is worth noting that
narcotic drugs have a certain effect on the damage of the nervous system [103,104]. In
Molecules 2022, 27, 3909 12 of 23
one report of 2019, green tea polyphenols (GTP) (25 mg/kg, i.g., for 7 days) could im-
prove cognitive impairment caused by isoflurane by regulating oxidative stress [105].
4.7. Effects on the Immune System

To date, there has been the little pharmacological study of green tea on the immune
system. EGCG (2.5 µM~10 µM) could inhibit the proliferation of spleen T cells in C57BL
mice in a dose-dependent manner. This mechanism may be related to the inhibition of
IL-2/IL-2 receptor signaling [106]. Other research data indicated that EGCG could induce
Foxp3 expression through a novel epigenetic mechanism, thereby inducing regulatory
T cells [107]. In 2014, Balaji J et al. found that green tea water extract can significantly
reduce the mortality of mice with anaphylactic shock induced by compound C48/80. This
finding provided experimental support for green tea in the treatment of asthma and allergic
rhinitis [108]. Wu et al. also reported that EGCG showed positive effects on experimental
autoimmune encephalomyelitis (EAE) mice by inhibiting T cell proliferation [109].
4.8. Other Pharmacological Effects

In addition to the pharmacological effects summarized above, green tea also possesses
several other aspects of pharmacological activity. In 2004, Geetha T et al. explored the
relationship between the antioxidant activity of green tea polyphenols and their antimuta-
genicity through different in vitro antioxidant methods and the highly standardized Ames
microsomal test system. Finally, it was found that its in vitro antioxidant activity was closely
related to its anti-mutagenic effect [110]. In 2005, Santhosh KT et al. first reported that
green tea polyphenols inhibited the mutagenicity of tobacco in a concentration-dependent
manner through its inhibition of nitrosation [111]. Apart from these, in in vivo experiments,
it was observed that thyroid peroxidase and 50-deiodinase I activities were reduced in
male albinism rats after treatment with high doses of green tea and catechins. These results
indicated that catechins in green tea extract may play an antithyroid role [112].
As we all know, the prevalence of hypertension is increasing year by year in every
country in the world. Diuretics, especially hydrochlorothiazide (HCTZ), are widely used
in the treatment of hypertensive patients with ischemic heart disease. At present, studies
have shown that the significant incidence of diuretic-induced hypokalemia with ventricular
ectopic activity is a serious problem in clinical medical treatment [113,114]. Chakraborty
et al. were the first to study the effects of green tea alone and in combination with hy-
drochlorothiazide (HCTZ) on diuretic activity. The results showed that green tea extract at
doses of 100 and 500 mg/kg showed significant diuretic activity; furthermore, green tea
extract also significantly reduced potassium loss in the combination group compared with
the HCTZ-treated group alone [115]. Susilowati et al. (2019) also reported that green tea
extract at a dose of 70 mg/kg had diuretic activity equivalent to furosemide, which may be
related to the increase of glomerular filtration rate by increasing blood flow and cardiac
output to the kidneys [116].
An in vivo experiment in rats demonstrated that green tea polyphenols have beneficial
effects on the bone mineral density of cancellous and cortical bone compartments in
ovariectomized rats [117]. Recently, Khademvatan S et al. demonstrated that green tea
compounds had anti-protozoal Leishmania effects through bioinformatics analysis [118].
Therefore, the pharmacological activities of green tea were summarized as shown in
Table 1 and Figure 9.
Molecules 2022, 27, 3909 13 of 23
Table 1. Pharmacological effects of green tea.
Pharmacological In Vitro/
Effects Detail Extracts/Compounds Minimal Active Concentration/Dose In Vivo Refs.
Inhibiting copper-catalyzed low-density lipoprotein (LDL)

Tea polyphenols 0.1 µg/mL In vitro [37]
lipid peroxidation
Scavenging DPPH radicals EGCG, ECG, EGC, and EC EC50 = 0.03, 0.04, 0.07, and 0.10 mol/mol In vitro [39]
DPPH, respectively
Antioxidant
effects Scavenging total oxy-radicals ECG and EGCG 0.348 ± 0.012, and 0.374 ± 0.020 TOSC/ µM In vitro [40]
Scavenging superoxide radicals TLPS, TFPS and TSPS 0.5 µg/mL~100 µg/mL In vitro [41]
Increasing the activity of antioxidant enzymes Green tea extract 125, 625 and 1250 mg/kg (i.g., for four weeks) In vivo [42]
Protecting against hepatotoxicity caused by excess acetaminophen
Green tea extract 10 mg/L In vivo [43]
(APAP) in mice
Inhibiting migration and invasion of tumor cells inhibited the growth
EGCG IC50 = 57.2%, and 29.3%, (48 h), respectively In vitro [46]
of HeLa cells
Inhibiting lung and liver metastasis in BALB/c mice with 4T1 tumors Green tea extract 0.06~0.125 mg/mL, respectively In vivo [47]
Inducing apoptosis in colon cancer cells by modulating Akt, ERK1/2
EGCG 100 or 200 µM In vitro [48]
and p38 MAPK signaling pathways
Inducing apoptosis in ovarian cells Green tea extract 0.1, 1, 10, 100, and 200 µg/mL, respectively In vitro [49]
Anticancer
effects Inhibiting the growth of HuH7 cells and HCC cells EGCG IC50 = 25, 84 µg/mL, respectively In vitro [50]
Inhibiting the growth of androgen-sensitive and androgen-sensitive
EGCG 10 µg/mL~80 µg/mL In vitro [51]
human prostate cancer cells (PCA)
Inhibiting the growth of gastric cancer cell line NCI-N87 in a time- and
EGCG 0~100 µM In vitro [52]
dose-dependent manner
Inhibiting the growth of oral cancer tumors Green tea polyphenols 200 mg/kg In vitro [54]
Inhibiting cyclooxygenase-2 in non-small cell lung cancer cells Green tea polyphenols 0, 10, 20, and 40 µg/mL, respectively In vitro [55]
Increasing insulin sensitivity in rats Green tea polyphenols 0.75% In vivo [58]
Improving insulin sensitivity and lipid distribution Green tea extract 80 mg/kg (i.g., for 12 weeks) In vivo [60]
Anti-diabetic Improving glucose metabolism Green tea extract 75 mg/kg (i.g., for 30 days) In vivo [61]
effects
Promoting insulin secretion The water-soluble 50 µg/mL~200 µg/mL In vitro [62]
polysaccharide 7WA
Alleviating maternal diabetes-induced neural tube defects EGCG 10 µM In vivo [66]
Molecules 2022, 27, 3909 14 of 23
Table 1. Cont.
Pharmacological Detail Extracts/Compounds Minimal Active Concentration/Dose In Vitro/ Refs.

Effects In Vivo
Inhibiting Helicobacter pylori activity EGCG MIC90 = 50~100 µg/ml In vitro [67]
Inhibiting the survival of Mycobacterium tuberculosis in macrophages EGCG 0~60 µg/mL In vitro [68]
Antibacterial Inhibiting S. aureus activity EGCG MIC90 = 58 mg/L In vitro [70]
effects
Inhibiting skin pathogens activity Green tea extract MIC = 0.156~0.313 mg /mL In vitro [71]
Green tea extract MIC = 250~1000 mg/mL, 125~500 mg/mL,
Inhibiting Porphyromonas gingivalis activity and EGCG In vitro [74]
respectively
Inhibiting HIV-1 integrase activity EGCG and GC IC50 = 0.96, 0.56 µmol/L, respectively In vitro [77]
Inhibiting influenza A virus activity EGCG EC50 = 22~28 µM In vitro [79]
EC50 = 5.02, 5.681, 19.8, and 10.76 µg/mL,
Antiviral effects Inhibiting the production of hepatitis B virus (HBV) Green tea extract In vitro [80]
respectively
Inactivating the Foodborne viruses, such as human Novo virus (NoV)
Green tea extract 10 mg/mL (for 30 min) In vitro [81]
and hepatitis A virus (HAV)
Inhibiting ZIKV entry into host cells EGCG Not mentioned In vitro [83]
Improve learning and memory in aged rats through the
Green tea extract 0.5% (i.g., for 8 weeks) In vivo [87]
antioxidant defense
Improve memory and hippocampal LTP in AD mice through the
L-theanine 12.5 µM~50 µM In vivo [88]
dopamine D1/5-PKA pathway
Neuroprotective effect on neurotoxins in mice and rat EGCG Not mentioned In vivo [90]
Protect dopamine neurons in 6-OHDA-treated PD rat models Green tea polyphenols 450 mg/kg/day In vitro [92]
Improve nerve redox imbalance and mitochondrial dysfunction by
Green tea polyphenols 10, 20, and 40 µg/mL, respectively In vitro [93]
Neuroprotective regulating circadian rhythm
effects Reduce neuronal damage after cerebral ischemia EGCG 50 mg/kg In vivo [95]
Improve the spatial cognitive ability after chronic
Green tea polyphenols 400 mg/kg In vivo [96]
cerebral hypoperfusion
Inhibiting HO-1 expression and activating ERK1/2 pathway Theanine 1 mg/kg In vivo [97]
Reduces (DDT)-induced cell death in dopaminergic SHSY-5Y cells EGCG 1, 3 and 10 µM In vitro [100]
Protecting against lead-induced brain oxidation and DNA damage in rats Green tea extract 5 g/L In vivo [102]
Improve cognitive impairment caused by isoflurane by regulating
Green tea polyphenols 25 mg/kg (i.g., for 7 days) In vivo [105]
oxidative stress
Molecules 2022, 27, 3909 15 of 23
Table 1. Cont.
Pharmacological Detail Extracts/Compounds Minimal Active Concentration/Dose In Vitro/ Refs.

Effects In Vivo
Inhibit the proliferation of spleen T cells in C57BL mice EGCG 2.5 µM~10 µM In vivo [106]
Inducing regulatory T cells EGCG 2%, w/v In vitro [107]
Effects on the
immune system Reduce the mortality of mice with anaphylactic shock induced by
Green tea extract 11, 13, and 15 mg/mL In vivo [108]
compound C48/80
Improve T-cell-mediated autoimmune diseases EGCG 0.3% In vivo [109]
Inhibited the mutagenicity of tobacco in a
Green tea polyphenols 50 mg/plate In vitro [111]
concentration-dependent manner
Other 1.25 g%,
Anti-thyroid effect Green tea extract In vivo [112]
pharmacological 2.5 g%, and 5.0 g%, respectively
effects Diuretic activity Green tea extract 100~500 mg/mL In vivo [115]
Bone-protective effect green tea polyphenols 0.1% or 0.5% concentration In vivo [117]
Anti-protozoal Leishmania effect EGCG and ECG IC50 = 27.7, 75 µM, respectively In vitro [118]
and cardiac output to the kidneys [116].
An in vivo experiment in rats demonstrated that green tea polyphenols have benefi-
cial effects on the bone mineral density of cancellous and cortical bone compartments in
ovariectomized rats [117]. Recently, Khademvatan S et al. demonstrated that green tea
Molecules 2022, 27, 3909 compounds had anti-protozoal Leishmania effects through bioinformatics analysis 16[118].
of 23
Therefore, the pharmacological activities of green tea were summarized as shown in Table
1 and Figure 9.
Figure
Figure 9.
9. Pharmacological
Pharmacological effects
effects of
of green tea.
green tea.
5. Toxicology
Table 1. Pharmacological effects of green tea.
Pharmacologic Green tea is a popular beverage, especially

Extracts/Compou in China
Minimal and Japan.InThere
Active are no reports
Vitro/In
Detail
of clinical toxicity on whether there is a health hazard in drinking a large amount ofRef. green
al Effects nds Concentration/Dose Vivo
tea every day. In 2008, Chengelis et al. first conducted safety studies on standardized green
Inhibiting copper-catalyzed low-
tea catechin (GTC) preparations, as well as heat-sterilized (GTC-H) and non-heat-sterilized
density lipoprotein
(GTC-UH) (LDL) lipid Tea polyphenols
preparations, and found that the level0.1 μg/mL In vitroeffects of
of no observed adverse [37]
the
peroxidation
three preparations (NOAEL) was 2000 mg/kg/day [119]. Another study demonstrated
that GTC-H did notEGCG, affect embryonic EC50 = 0.03, 0.04, 0.07, and
ECG, EGC,development in female rats. Its NOAEL was also
Scavenging2000
DPPH radicals[120]. Furthermore, Hsu et al.
mg/kg/d 0.10used
mol/mol In vitroparadigm
a subacute exposure [39]to
and EC
evaluate that green tea extract (2500 mg/kg, DPPH,
i.g., respectively
for 28 days) would not cause death or
toxicity in ICR mice [121]. These valuable data±provide
0.348 the0.374
0.012, and basis ±for the safe application of
Antioxidant Scavenging green
total oxy-radicals ECG
tea extract in food and EGCG
production. In vitro [40]
0.020 TOSC/ μM
effects Green tea is often TLPS,
developed
TFPSasand
a weight-loss beverage, and they are usually considered
Scavenging superoxide radicals
as safe. However, the United 0.5 μg/mL~100
States Pharmacopoeia μg/mL
(USP) has conductedIn vitro [41]
a safety review
TSPS
and counted adverse events (AEs) after the use of high-dose GTE preparations, most of
Increasing the activity of 125, 625 and 1250 mg/kg
which were liver injury Green tea [122–125].
reports extract In vivoLambert[42]
In 2010, in an in vivo experiment, et al.
antioxidant enzymes (i.g., for four weeks)
reported for the first time that plasma alanine aminotransferase (ALT) in male CF-1 mice
Protecting against hepatotoxicity
increased 138 times after treatment with high-dose EGCG (1500 mg/kg, i.g., for 7 days).
caused by excess
Therefore, they came Green
acetaminophen to the tea extract that high10
conclusion mg/Lof EGCG had aInhepatotoxic
doses vivo [43]
effect.
(APAP)
Thisinmechanism
mice of toxicity might be related to the induction of oxidative stress in the liver.
Inhibiting migration
However, andthe
invasion
observed toxic doses were much higher than normal tea consumption [126]. In
Anticancer IC50 = 57.2%, and 29.3%,
of tumor cells
2018,inhibited
Hu et al.the
evaluated the EGCG
safe dosage of green tea for adults based on In toxicological
vitro [46]
data
effects (48 h), respectively
growth and AEs.cells
of HeLa The safe intake for adults should be controlled below 338 mg EGCG/day [127].
Furukawa et al. investigated whether EGCG could cause oxidative damage to in vitro
bovine thymus DNA under the action of metal ions and H2 O2 oxidative stress. They
observed that EGCG promoted the formation of 8-oxide, a characteristic oxidative damage
to DNA that is strongly associated with mutations and cancer [128]. Therefore, they came to
the conclusion that that this oxidative damage to EGCG could be considered as a potential
predisposing factor for EGCG carcinogenicity [129]. One study showed that EGCG (20,
40 and 80 µM, 10, 60, and 240 min) caused DNA damage in both human lymphocytes
and Nalm6 cells in a dose-dependent manner. When the maximum dose of EGCG was
Molecules 2022, 27, 3909 17 of 23
100 µM, the survival rate of Nalm6 and human lymphocyte decreased by 50% and 25%,
respectively [130].
6. Conclusions
In this paper, the phytochemical constituents and pharmacological activities of green
tea were systematically and comprehensively reviewed. Catechin, caffeine, theanine,
tea polysaccharide, and other chemical components in green tea have pharmacological
activities and health care functions, such as antioxidant, anti-tumor, hypoglycemic, and so
on. As a natural antioxidant, tea polyphenols have been widely used in the food industry
and cosmetics. In addition, the catechins in green tea also play an important role in the
prevention and treatment of diabetes, hepatitis, microbial/viral infections, cancer, and
skin inflammation.
In 2006, the FDA approved “Veregen ointment”, a green tea extract external prepa-
ration, for clinical use and it has already appeared on the market in the United States.
However, the research on the pharmacological activity of green tea is still in the laboratory
research stage. Therefore, how to carry out in-depth research on the mechanism of green
tea active ingredients and realize the conversion from research to clinical application is still
a major challenge facing researchers. Finally, there are few reports on toxicological studies
of green tea, mainly related to hepatotoxicity and cytotoxicity. Therefore, toxicity studies
are still a potential research area in the future.
7. Perspectives
First, there have been numerous studies to prove that many chemical components
in green tea have significant pharmacological activities. However, little is known about
the relationship between the chemical structure, physicochemical properties of these com-
ponents, and pharmacological activity. EGCG is the most biologically active catechin in
green tea. Chao et al. found that the solubility of EGCG after acetylation (pEGCG) was
significantly improved, and activity analysis experiments showed that pEGCG was more
effective in preventing neurodegenerative diseases than EGCG [131]. Therefore, in addition
to the solubility of the compound, the relationship between its molecular weight, bonding
type, functional group distribution, and physiological activity needs to be further explored.
Second, tea polyphenol (TP) is a general term for polyhydroxy phenol compounds
contained in green tea. It is the main active ingredient of green tea and has various pharma-
cological effects such as scavenging free radicals and anti-tumor. However, tea polyphenols
have poor lipid solubility, low bioavailability, and are easily oxidized, which limits their
application in the pharmaceutical and food industries. At present, some new preparation
technologies such as liposome and nanoemulsion have been used to improve the bioavail-
ability of tea polyphenols in vivo [132,133]. These technologies generally have the problems
of complicated preparation processes and residual organic solvents. Therefore, based on a
comprehensive variety of technologies, it is necessary to introduce new technologies to give
full play to the active role of green tea polyphenols in disease prevention and treatment.
Third, China is the world’s largest exporter of green tea. The export volume of green
tea accounts for more than 80% of the international market, but the average export price
is generally lower than the top five in the world. Therefore, the tea industry should be
promoted to form a set of standardized, engineered, and large-scale new industrial models,
and ultimately to achieve modernization and internationalization. (1) Standardization of
evaluation methods of green tea. Emerging detection technologies, such as electronic eyes,
electronic tongues, and electronic noses, are used to detect the color, taste, and aroma of tea
soup. It is simple, convenient, low cost, gives reliable results, highly repeatable, and has a
broad application prospect in the field of green tea quality assessment. (2) Improvement
of quality and safety standards of green tea. Due to the large number and variety of
green tea in China, it is unrealistic to uniformly specify the name, quality, and grade of all
green tea products under a single standard. Therefore, on the one hand, according to the
quality characteristics of different varieties of green tea, other standards in this series can
Molecules 2022, 27, 3909 18 of 23
be continuously formulated and supplemented, so that the green tea quality standards can
be continuously enriched and improved. On the other hand, it is necessary to continuously
strengthen the integration between the Chinese tea standard system and international
standards, and the adaptability to the market economy.
Author Contributions: T.Z.: collecting and organizing literature, and writing the draft manuscript;
C.L.: reviewing and editing; S.W.: completing tables and figures; X.S.: designing the overall structure
of the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by The National Natural Science Foundation of China (grant no.
U1804179), The Key Scientific and Technological Projects in Henan Province (grant no. 202102310190),
The Nanhu Scholars Program for Young Scholars of Xinyang Normal University (grant no. 2018001),
and Youth Foundation of Xinyang Normal University (grant no. 2022-QN-049).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
ROS reactive oxygen species
MMP-9 matrix metalloprotein-9
TIMP-1 tissue inhibitor of metalloproteinase-1
HT-29 human colorectal adenocarcinoma grade II
Akt extracellular signal-regulated kinase
ERK1/2 extracellular signal-regulated kinase 1/2
MAPK mitogen-activated protein kinase
EIA enzyme linked immunosorbent assay
VEGF vascular endothelial growth factor
KLF4 kruppel-likefactor 4
4-NQO 4-Nitroquinoline 1-oxide
COX-2 cyclooygenase-2
ANX1 annexin-1
PPAR peroxisome proliferator-activated receptors
LPL lipoproteinlipase
GLUT-4 glucose transporter-4
cAMP cyclic AMP
TACO tryptophan-aspartate containing coat protein
HSCCC high-speed counter-current chromatography
LTP long-term potentiation
PKA protein kinase A
6-OHDA 6-hydroxydopamine
HO-1 heme oxygenase-1
DDT dichlorodiphenyl-trichloroethane
IL-2 interleukin 2
p53 protein 53
p38 protein 38
HIV-1 human immunodeficiency virus-1
AD Alzheimer’s disease
PD Parkinson’s disease
Bax BCL2-Associated X Protein
Bcl-2 B-cell lymphoma-2
Molecules 2022, 27, 3909 19 of 23
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Molecules: Green Tea (Camellia Sinensis) : A Review of Its Phytochemistry, Pharmacology, and Toxicology

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Molecules 2022, 27, 3909. https://doi.org/10.3390/molecules27123909 https://www.mdpi.com/journal/molecules

3.1. Tea Polyphenols

3.1.1. Catechins (1–5)

3.1.2. Flavonoids (6–25)

(+)−Cateehin (C) (−)−Epicatechin (EC) (−)−Epigallocatechin (EGC)

(+)−Cateehin (C) (−)−Epicatechin (EC) (−)−Epigallocatechin (EGC)

(−)−Epicatechin gallate (ECG) (−)−Epigallocatechin gallate (EGCG)

3.1.2. Flavonoids (6–25)

3.1.2. Flavonoids (6–25)

Molecules 2022, 27, 3909 4 of 23

Caffeine Theophylline Theobromine

3.3. Amino Acids (35–39)

Serine Aspartic acid

3.7. Mineral Elements

Dimethyl sulfide Pentanal 8-Octadecenoic acid methyl ester

Dibutyl phthalate Hexanal Acetone

Heptanal 2-methylbutyraldehyde 3-Methylbutyraldehyde

Methyl hexadecanoate Acetic acid

1-Ethylpyrrole 2-Methylpropionaldehyde Naphthalene

3.6. Organic Acids (57–65)

Oxalic acid Tartaric acid Formic acid L-malic acid

Ascorbic acid Lactic acid Citric acid

Succinic acid Fumaric acid

at concentrations ranging from 0.5~100 µg/mL, could exhibit a dose-dependent superoxide

4.2. Anticancer Effects

4.3. Anti-Diabetic Effects

4.4. Antibacterial Effects

4.5. Antiviral Effects

4.6. Neuroprotective Effects

4.7. Effects on the Immune System

4.8. Other Pharmacological Effects

Table 1. Pharmacological effects of green tea.

Inhibiting copper-catalyzed low-density lipoprotein (LDL)

Pharmacological Detail Extracts/Compounds Minimal Active Concentration/Dose In Vitro/ Refs.

Pharmacological Detail Extracts/Compounds Minimal Active Concentration/Dose In Vitro/ Refs.

Pharmacologic Green tea is a popular beverage, especially

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