Potential Therapeutic Effects of Funct

Pharmacology & Therapeutics 142 (2014) 183195
Contents lists available at ScienceDirect
Pharmacology & Therapeutics

journal homepage: www.elsevier.com/locate/pharmthera
Associate editor: I. Kimura
Potential therapeutic effects of functionally active compounds isolated

from garlic
Hyung-Mun Yun a,1, Jung Ok Ban a,1, Kyung-Ran Park a, Chong Kil Lee a, Heon-Sang Jeong b,
Sang Bae Han a, Jin Tae Hong a,
a
b
College of Pharmacy and Medical Research Center, Chungbuk National University, 48 Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, Republic of Korea
Department of Food Science and Technology, Chungbuk National University, Chungbuk 361-763, Republic of Korea
a r t i c l e
i n f o
Available online 11 December 2013

Keywords:
Garlic
Organosulfur compounds
Cancer
Cardiovascular disorders
Neurological diseases
Liver diseases
Allergy
Arthritis
a b s t r a c t
The medicinal properties of functionally active organosulfur compounds such as allin, diallyl disulde,
S-allylmercaptocysteine, and S-trityl-L-cysteine isolated from garlic have received great attention from a large
number of investigators who have studied their pharmacological effects for the treatment of various diseases.
These organosulfur compounds are able to prevent for development of cancer, cardiovascular, neurological,
and liver diseases as well as allergy and arthritis. There have been also many reports on toxicities and pharmacokinetics of these compounds. The aim of this study is to review a variety of experimental and clinical reports, and
describe the effectiveness, toxicities and pharmacokinetics, and possible mechanisms of pharmaceutical actions
of functionally active compounds isolated from garlic.
2013 Elsevier Inc. All rights reserved.
Contents
1.
Introduction . . . . . . . . . . . . . . . . . . . . .
2.
Components of garlic . . . . . . . . . . . . . . . . .
3.
Pharmaceutical effect of garlic on cancer development . .
4.
Pharmaceutical effect of garlic on cardiovascular disorders
5.
Pharmaceutical effect of garlic on neurological diseases . .
6.
Other pharmaceutical effects of garlic . . . . . . . . . .
7.
Pharmacokinetics . . . . . . . . . . . . . . . . . . .
8.
Toxicity and safety . . . . . . . . . . . . . . . . . .
9.
Perspective . . . . . . . . . . . . . . . . . . . . . .
Conict of interest . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Historically, garlic has been revered as part of a healthful diet. The
earliest known references indicate that garlic formed part of the daily
diet of many Egyptians (Block, 1985). It was fed particularly to the
working class involved in heavy labor, as in the building of the pyramids
(El-Bayoumy et al., 2006). Indeed, a recurring theme throughout early
history is that garlic was given to the laboring classes, presumably to
Corresponding author. Tel.: +82 43 261 2813; fax: +82 43 268 2732.
E-mail address: jinthong@chungbuk.ac.kr (J.T. Hong).
1
These authors contributed equally to this work.
0163-7258/$ see front matter 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.pharmthera.2013.12.005
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maintain and increase their strength, thereby enabling them to work

harder and be more productive (Rivlin, 2001). Ancient medical texts
from Egypt, Greece, Rome, China, and India prescribed garlic for a
number of applications including improving performance, reducing
infections, and protection against toxins (Rivlin, 2006). These medicinal
properties, coupled with its savory characteristics, have made garlic
a true cultural icon in many parts of the world. Thus, garlic is used
traditionally as a avor enhancer and has been recognized as not only
a common food additive but also a potent therapeutic agent.
The whole bulbs of garlic contain alliin, -glutamyl-S-allylcysteine,
S-methylcysteine sulfoxide, S-trans-1-propenylcysteine sulfoxide,
S-2-carboxypropylglutathione and S-allylcysteine (Amagase, 2006;
184
H.-M. Yun et al. / Pharmacology & Therapeutics 142 (2014) 183195
Kimbaris et al., 2006). Recently, a novel organosulfur compound,

thiacremonone (2,4-dihydroxy-2,5-dimethyl-thiophene-3-one) was
isolated and identied from heated garlic (Ban et al., 2007). Chemical
composition of the preparations obtained by extraction of garlic fractions depends on the extraction conditions: temperature, time and
solvent's polarity. The content of organosulfur compounds in garlic
bulbs changes during cultivation and storage (Lawson et al., 1991). Its
biological activities depend on many factors, including country of origin
and various processing methods of garlic to isolate new organosulfur
compounds and to decompose organosulfur compounds. Therefore,
the development of methods for determination of organosulfur
compounds in garlic and selecting garlic is apparently great importance
for evaluating the biological quality of garlic and garlic products.
Organosulfur compounds have been attributed to the medicinal
properties and health benets of garlic. Several recent studies have
shown that these organosulfur compounds have anti-cancer, anticardiovascular disease, anti-neurological disease, and anti-liver disease
effects, as well as effects for prevention of allergy and arthritis

(Amagase et al., 2001; Amagase, 2006). While these effects are wellknown, the exact mechanisms of action have not yet been established.
In the present paper, the aim of this study is to review data from a variety of experimental and clinical reports and describe the effectiveness
and possible mechanisms of action on how garlic showed the medical
properties.
2. Components of garlic
Among the several functional compounds of garlic (Table 1), alliin is
the most abundant organosulfur compound in whole garlic. It is a derivative of the amino acid cysteine. Lawson (1998) found that fresh garlic
contains alliin (614 mg/g). 25.6530.03 mg/g alliin was detected in
Korean garlic cloves and 6.7 mg/g in Korean garlic bulbs (Yoo et al.,
2010). 16.721.4 mg/g alliin was also detected in dried garlic cloves
and 5.39.4 mg/g in fresh Germany garlic cloves (Allium sativum L. var.
Table 1
Chemical structure and quantity of some volatile organosulfur compounds present in garlic.
Sulfur components
Contents (mg/g)
Origin of garlic
Isolation solution
References
Alliin
2530
6.7
16.721.4
5.39.4
22.1
Korean garlic cloves

Korean garlic bulbs
Germany dried garlic
Germany fresh garlic
Japanese garlic
Water
Water
Water
Water
Water
Yoo et al., 2010

Yoo et al., 2010
Bloem et al., 2011
Bloem et al., 2011
Shimpo et al., 2002
2.34.6
7.7
6.17.7
2.43.5
5.16.6
5.05.3
0.010.02
0.000.02
0.000.02
0.020.23
Korean garlic
Australian garlic
USA garlic
Switzerland garlic
Chinese garlic
Japanese garlic
Greek garlic
Greek garlic
Greek garlic
Korean garlic
Water
Water
Water
Water
Water
Water
Diethyl ether
Ethyl acetate
Hexane
Dichloromethane
Yoo et al., 2010

Sterling & Eagling, 2001
Koch & Lawson, 1996
Ziegler & Sticher, 1989
Lawson et al., 1991
Ueda et al., 1991
Kimbaris et al., 2006
Lee et al., 2003
0.080.28
0.060.231
0.070.26
0.570.89
Greek garlic
Greek garlic
Greek garlic
Korean garlic
Diethyl ether
Ethyl acetate
Hexane
Dichloromethane

Lee et al., 2003
0.000.20
0.010.22
0.010.18
0.110.39
Greek garlic
Greek garlic
Greek garlic
Korean garlic
Diethyl ether
Ethyl acetate
Hexane
Dichloromethane

Lee et al., 2003
0.17
0.17
0.12
0.47
Japanese garlic
Japanese garlic
Japanese garlic
Japanese garlic
Soybean oil
Rice oil
Soybean oil
Rice oil
Naznin et al., 2008

Naznin et al., 2008
Naznin et al., 2008
Naznin et al., 2008
0.45
0.360.60
USA garlic
Korean garlic
Water
Water
Amagase & Milner, 1993

Yoo et al., 2010
0.7 (g/g)
Korean garlic
Ethyl acetate
Hwang et al., 2007
(MW: 62.28)
Allicin
(MW: 162.27)
Diallyl sulde
(DAS)
(MW: 114.2)
Diallyl disulde (DADS)
(MW: 146.28)
Diallyl trisulde (DATS)
(MW: 178.34)
E-Ajoene
Z-Ajoene
(MW: 234.4)
S-allyl cysteine (SAC)
(MW: 161.22)
Thiacremonone
(MW: 160.19)
Thermidrome) (Bloem et al., 2011). Shimpo et al. (2002) found

22.1 mg/g alliin in water extracts of heated Japanese garlic powder.
Allicin features the thiosulnate functional group, R-S(O)-S-R
(Table 1). The compound is not present in garlic unless tissue damage
occurs (Block, 1985), and is formed by the action of the enzyme alliinase
on alliin (Block, 1985). It is considered that 1 mg alliin is equivalent
to 0.45 mg allicin (European Scientic Cooperative of Phytotherapy.
Monographs on the medicinal uses of plant drugs: fascicules 1 and 2
(1996); Barnes et al., 2007). The amount of allicin which was known as
a major bioactive compound of garlic and garlic preparations is about
2.34.6 mg/g in Korean garlic (Yoo et al., 2010). About 79 mg/g allicin
was detected in Australian garlic. Sterling and Eagling (2001) reported
that allicin was detected about 6.17.7 mg/g in the USA garlic, 2.4
3.5 mg/g in Switzerland garlic (Ziegler & Sticher, 1989), 5.16.6 mg/g
in Chinese garlic and 5.16.6 mg/g in Japanese garlic (Ueda et al.,
1991). Commercial garlic preparations are often standardized on the
content of sulfur-containing constituents, particularly to alliin, or on
the allicin yield (Barnes et al., 2007).
Diallyl sulde (DAS) is easily transformed from allicin (Sengupta
et al., 2004) (Table 1). Kimbaris et al. (2006) found that garlic oil contains DAS (23 g/g) by simultaneous distillation extraction, analyzed
by FT-Raman spectroscopy. Kimbaris et al. (2006) found that diethyl
ether, ethyl acetate or hexane extract or extracts of garlic were composed of DAS about 1020, 020 or 020 g/g, respectively. Lee et al.
(2003) found that dichloromethane extracts of Korean garlic were
composed of DAS about 0.020.23 mg/g.
Diallyl trisulde (DATS) begins its biochemical synthesis with
-glutamyl-S-alk(en)yl-L-cysteine, which is hydrolyzed and oxidized
to produce alliin (Block, 1985) (Table 1). Alliin is the odorless precursor
of DATS. Processing of garlic (cutting or chewing) generates a vacuolar
enzyme (allinase), which acts upon alliin to give rise to allicin and
other alkyl alkane-thiosulnates (Block, 1985). Allicin and related
thiosulnates are decomposed to yield various organosulfur compounds including DATS. Kimbaris et al. found that diethyl ether, ethyl
acetate or hexane extracts of garlic were composed of DATS about
0200, 10220 or 1180 g/g, respectively (Kimbaris et al., 2006). Lee
et al. found that dichloromethane extracts of Korean garlic were composed of DATS about 0.110.39 mg/g (Lee et al., 2003).
Ajoene (4,5,9-trithiadodeca-1,6,11-triene-9-oxide) is the degradation product of allicin (Table 1). Incubation temperature is a very important factor for ajoene formation. When incubation temperature was at
40, 60 and 80 C, the amount of ajoene concentration also increased
gradually, with the highest amount of E-ajoene (172.0 g/g of garlic)
and Z-ajoene (476.3 g/g of garlic) found in Japanese garlic with
rice oil at 80 C, indicating its optimal temperature (Naznin et al.,
185
2008). Soybean oil was composed of E-ajoene (172.0 g/g of garlic)

and Z-ajoene (120 g/g of garlic).
S-allyl cysteine (SAC), a major transformed product from glutamyl-S-allyl-L-cysteine, is the water-soluble organosulfur compounds and its concentration increases through a long-term extraction
in an aqueous medium (Table 1). SAC is detected in the blood, and its
blood concentration and pharmacokinetic parameters are wellassociated with doses of orally administered SAC in animal studies
(Amagase, 2006). Amagase and Milner found that aged garlic contains
SAC about 0.45 mg/g (Amagase & Milner, 1993). Yoo et al. (2010)
found that water extracts of Korean garlic were composed of SAC
about 0.360.60 mg/g.
Diallyl disulde (DADS) is an organosulfur compound found in
plants of the genus Allium (Table 1). Along DATS and diallyl tetrasulde,
it is one of the principal components of the distilled oil of garlic. It
is yellowish water in soluble liquid and has a strong garlic odor. It is
produced during the decomposition of allicin, which is released during
incision of garlic and other plants of the Alliaceae family (Amagase
et al., 2001). DADS has many health benets from garlic, but it is also
an allergen causing garlic allergy. Highly diluted, it is used as a avoring
in the food. Kimbaris et al. found that diethyl ether, ethyl acetate or
hexane extracts of garlic were composed of DADS 80280, 60231 or
70260 g/g, respectively (Kimbaris et al., 2006). In addition, Lee et al.
found that dichloromethane extracts of Korean garlic were composed
of DADS about 0.570.89 mg/g (Lee et al., 2003).
Thiacremonone (2,4-dihydroxy-2,5-dimethyl-thiophene-3-one)
was isolated and identied as a novel and major organosulfur compound (0.3%) in High-Temperature-High-Pressure (HTHP)-treated garlic (Hwang et al., 2006) (Table 1). The heated samples were juiced and
then ltered on a Buchner funnel under a vacuum. Heated garlic juice
was partitioned consecutively in a separating funnel using ethyl acetate.
Isolation of the compounds from the ethyl acetate layer of heated garlic
juice was subjected to column chromatography on silica gel. This fraction was puried by preparative RP-HPLC on a Younglin SP930D Instrument. It was recently found that heated Korean garlic contains
thiacremonone about 0.7 g/g (Hwang et al., 2006).
3. Pharmaceutical effect of garlic on cancer development
3.1. Anti-cancer effect of garlic in epidemiological studies
Over the last 30 years, there have been many literature reports of
epidemiological studies indicating that a garlic-rich diet decreases risk
of some cancers such as gastric, stomach, and colon as shown in
Table 2. Those who consumed garlic more than 3 times/week have
Table 2
Epidemiological studies showing anticarcinogenic properties of garlic.
OSCs
Type of cancer
Country
Cases/controls
OR
OR (95% CI)
References
Garlic
Garlic
Garlic
Garlic
Garlic and onion
Garlic and onion
Garlic
Garlic
Garlic
Garlic
Garlic
Garlic and onion
Garlic
Garlic
Garlic
Garlic
Garlic
Gastric
Garstric
Garstric
Garstric
Garstric
Garstric
Stomach
Stomach
Stomach
Stomach
Stomach
Stomach
Colon
Colon
Colon
Colon
Colon
Iran
Korea
Uruguay
Venezuela
Serbia
Italy
Lithuania
China
China
China
China
10 Europe
Argentina
USA
Switzerland
USA
Netherlands
217/394
136/136
160/320
292/485
102/204
126/561
379/1137
750/750
98/196
187/333
201/201
330/521,457
110/220
1192/1192
223/491
212/3500
443/3123
0.35
0.5
0.67
0.5
0.11
0.53
0.5
0.68
0.5
0.66
0.21
0.77
0.22
0.7
0.39
0.68
1.36
0.35 (0.130.95)
0.50 (0.270.91)
0.67 (0.381.18)
0.5 (0.30.8)
0.11 (0.020.6)
0.53 (0.250.82)
0.50 (0.231.08)
0.68 (0.371.26)
0.50 (0.190.81)
0.66 (0.371.17)
0.21 (0.090.50)
0.77 (0.501.20)
0.22
0.7
0.39
0.68
1.36
Pourfarzi et al., 2009

Kim et al., 2002
De Stefani et al., 2001
Munoz et al., 2001
Lazarevic et al., 2010
Palli et al., 2001
Zickute et al., 2005
Setiawan et al., 2005
Gao et al., 2002
Takezaki et al., 2001
Setiawan et al., 2005
Gonzalez et al., 2006
Iscovich et al., 1992
Le Marchand et al., 1997
Levi et al., 1999
Steinmetz et al., 1994
Dorant et al., 1996
OR, odds ratios.
F344 rat
67%
DAS, diallyl sulde; DADS, diallyl disulde; DATS, diallyl trisulde; S-allyl mercaptocysteine; SAC, S-allylycysteine; , Decrease; , Increase.
Daily for 8 w
Diet
1%
Garlic ethanol DMA-induced colon cancer
extract
Daily for 8 w
Oral
SAC
480 mg/kg
Human NSCLC A-549 xenograft
Ajoene
SAMC
SAC
SAC
SAC
DATS
DATS
DATS
Kim et al., 2007
BALB/CAnN-Foxn1 nude mice Tang et al., 2010

64%
Nishikawa et al., 2002

Liang et al., 2011
Chu et al., 2007
Howard et al., 2007
Tang et al., 2010
ICR mice
BALB/c athymic nude mice
BALB/c athymic nude mice
CB-17 SCID/SCID mice
BALB/CAnN-Foxn1 nude mice
95%
N 90%
62.40%
71%
42%
Apoptosis, caspase 3 and PARP1

Apoptosis and caspase 3 ; Bcl-2
Meteastasis ; E-cadherin
Proliferation ; PI3K/Akt, NF-B
and Cox-2
Proliferation ; PI3K/Akt, NF-B
and COX-2
Cell growth, AP-1 and b-actenin ; p21
Twice/w for 20 d
Daily for 16 d
Daily for 7 w
Daily for 28 d
Daily for 8 w
Topical
Oral
i.p.
Orogastric feeding
Oral
Thrice/w for 13 w
Twice/w for 20 w
4080 mg/kg
Oral
0.20.9 (g/mouse tissue) Topical
5 times/w for 4 w
Oral
40 mg/kg
250 (g)
300 mg/kg
1000 mg/kg
300 mg/kg
240 mg/kg
Singh et al., 2008

Shrotriya et al., 2010
TRAMP mice
ICR mice
2546%
7599%
50%
BALB/c nude mice
Kalra et al., 2006

Yang et al., 2001
Zhao et al., 2006
Wu et al., 2011
Chandra-Kuntal
& Singh, 2010
Shankar et al., 2008
Swiss albino mice
A/J mice
SCID mice
BALB/c mice
TRAMP mice
62%
63.40%
50%
41%
Apoptosis, p53 and p21; Bcl-2 and survivin

NNK-metabolizing enzyme activity
G1 phase arrest and p21WAF1
Apoptosis and sub-G1 arrest
Apoptosis STAT3, Bcl-2, Bcl-xL
and Survivin
Growth and TRAIL ; DR4, DR5
and caspase-8
Proliferation ; Cyclin B1
AP-1, COX-2, JNK and Akt
3 times/w for 28 w
Daily for 3 d
3 times/w for 21 w
Every 5 d for 32 d
3 times/w for 13 w
Topical
p.o.
Peritoneal cavity
p.o.
Gavage
DMBA-induced skin carcinogenesis

NNK-induced lung cancer
HL-60 xenograft
Mouse colon carcinoma CT26 allograft
Transgenic adenocarcinoma of mouse
prostate (TRAMP)
Human prostate cancer PC-3 xenograft
(orthotopic)
TRAMP
DMNA and TPA induced two-stage skin
papilloma model
Skin tumor
Human colon cancer SW620 xenograft
Human prostate cancer CWR22R xenograft
Human prostate cancer PC-3 xenograft
Human NSCLC A-549 xenograft
DAS
DAS
DADS
DATS
DATS
10 mg/kg
200 mg/kg
42 mg/kg
50 mg/kg
80 mg/kg
Duration
Administration
Doses and
concentrations
Cancer type
Table 3
In vivo laboratory studies showing anticarcinogenic properties of garlic and its constituents.
Preclinical studies have provided convincing evidence that several

natural organosulfur compound analogues are highly effective in
affording protection against cancer induced by different carcinogens in
different experimental animals listed in Table 3. DAS, DADS, DATS, ajoene,
SAC, and garlic extracts are documented to inhibit lung, liver, prostate and
skin tumor development (Shankar et al., 2008; Chandra-Kuntal & Singh,
2010; Wu et al., 2011). DAS topical treatment (10 mg/kg, 3 times/week
for 28 weeks) induced apoptosis and inhibited tumor growth through
modulation of p53 and Ras-induced signaling pathways including p21/
waf1, survivin, bcl-2, PI3K/Akt, and MAPKs in DMBA induced skin tumors
in Swiss albino mice (Kalra et al., 2006). DADS (42 mg/kg, 3 times/week
for 21 weeks) was protective against cancers of the human promyelocytic
leukemia HL-60 via G1 phase arrest and induction of p21/WAF1 expression (Zhao et al., 2006). DATS treatment (about 80 mg/kg, 3 times/week
for 13 weeks) suppresses prostate cancer development in transgenic adenocarcinoma of mouse prostate mice via a visible decrease in the levels
of pSTAT3 (Chandra-Kuntal & Singh, 2010). SAC treatment (240 mg/kg
and 480 mg/kg) in an vivo model of NSCLC A549-implanted nude mice
showed an anti-tumor effect, a decrease of 42 and 64% in tumor growth
by inhibition of proliferation of cancer cells via reduction of PI3K/Akt,
NF-B, and COX-2 expression (Tang et al., 2010). Garlic ethanol extract
inhibited DMH-induced overexpression of Activator Protein-1 (AP-1)
and -catenin genes related to cell proliferation that also upregulated
the expression of p21Waf1/Cip1 mRNA and a cell cycle-regulating gene
(Kim et al., 2007). Naturally occurring organosulfur compound analogues
can also suppress proliferation of cancer cells in culture listed in Table 4
including human colon, lung, prostate, liver, breast, keratinocytes,
leukemia, and gastric cancer cells.
DAS and DATS suppressed the proliferation and induced apoptosis of
human colon cancer cells through oxidative modication of -tubulin
(Hosono et al., 2005). DAS decreased the cell growth of HEK 293T
keratinocytes through inhibition of cyclooxygenase-2 (Elango et al.,
2004). DAS and garlic extract increased cell death through regulation
of the expression of Bcl-2, Bax, and p53 in NCI-H460 and NCI-H1299
non small cell lung cancer cell lines (Hong et al., 2000). DADS increased
apoptosis through induction of the G2/M cell cycle arrest and regulation
of the expression of apoptosis regulatory proteins in human A549, NCI
H460 and NCI1299 lung cancer cells (Hong et al., 2000; Wu et al.,
2005). In addition, DADS inhibited proliferation via induction of the
expression of p21/waf1 and the G2/M cell cycle arrest in human colon
cancer cells (Robert et al., 2001; Filomeni et al., 2003). Similarly DATS
was shown to induce apoptosis and G1 phase arrest in human colon
cancer cells (Hosono et al., 2005; Wu et al., 2005). DATS induced apoptosis through modulation of Bcl-2 expression and phosphorylation of
JNK and ERK in human prostate PC-3 cells (Xiao et al., 2004). This is a
novel aspect in the biological prole of this garlic compound giving
new insights into the understanding of the molecular mechanisms of
Mechanisms
3.2. Anti-cancer effect of garlic in in vivo and in vitro studies
References
lower risk of gastric cancer than those who never or infrequently

consumed it (OR 0.42; P for trend b 0.01) (Pourfarzi et al., 2009).
A signicant decrease in the risk of gastric cancer was observed with
increased intake of garlic (OR = 0.50 [CI = 0.270.91]) (Kim et al.,
2002). Garlic consumption was strongly associated with a reduced risk
of stomach cancer (OR 0.67, 95% CI 0.381.18) (De Stefani et al.,
2001). Frequent consumption of garlic was negatively associated with
gastric cancer (OR 0.5, 95% CI 0.30.8) (Munoz et al., 2001). Allium vegetables (e.g. onion, garlic, leek) decreased the risk of stomach cancer
(OR 0.11; 95% CI 0.020.60) (Lazarevic et al., 2010). For gastric tumors,
a signicant protective effect was associated with frequent consumption of garlic (Palli et al., 2001). Stomach cancer risk was inversely associated with consumption of raw vegetables such garlic (OR = 0.59, 95%
CI = 0.370.96; 16 times/week vs. almost never) (Zickute et al.,
2005). Intakes of garlic were inversely associated with risk of colon
cancer (Iscovich et al., 1992; Le Marchand et al., 1997; Levi et al., 1999).
inhibition Animal model
Components
186
187
Table 4
In vitro laboratory studies showing anticarcinogenic properties of garlic and its constituents.
OSCs
Cancer cell type
IC50 (mM)
Treatment Mechanisms
time
References
DAS
HCT-15 and DLD-1 human colon tumor cells
N100
24 h
Hosono et al., 2005
30
2025
72 h
48 h
DADS
HEK 293T keratinocytes

NCI-H460 and NCI-H1299 non small cell lung
cancer cell line
Human A549 lung cancer
Apoptosis and G1 phase arrest ; Tubulin polymerization

Proliferation and Cox-2
Apoptosis, p53 and Bax Bcl-2
2550
48 h
Wu et al., 2005
N100
24 h
PC3 prostate cancer

HEK 293 T keratinocytes
Caco-2 and HT29 human colon cancer cells
HT29 human colon adenocarcinoma
35
16.1
b200
100
24 h
72 h
24 h
24 h
Apoptosis, intracellular ROS and G2/M cell cycle arrest

Apoptosis, G1 phase arrest ; Tubulin polymerization
Apoptosis ; Bcl-2
Proliferation and Cox-2
Proliferation and histone deacetylase activity ; p21/waf1
G2/M phase arrest and DNA fragmentation G2/M phase
arrest and DNA fragmentation G2/M phase arrest and
DNA fragmentation
Apoptosis, p53 and Bax ; Bcl-2
Apoptosis and sub-G1 arrest Apoptosis and sub-G1
arrest Apoptosis and sub-G1 arrest
Apoptosis ; STAT3 and Bcl-2
DATS
SAMC
SAC
Ajoene
NCI H460 and NCI1299 Non small cell lung cancer b5

Mouse CT26 colon cancer cells
20
48 h
24 h
DU145 LNCaP human prostate cancer
2040
24 h
Human BGC823 gastric cancer

2550
1015
72 h
24 h
Human HEK 293 T keratinocytes

DU145 and PC3 prostate cancer
J5 human liver tumor
HepG2 human hepatoma
SW480, SW620, Caco-2 human colorectal cancer
cellsSW480, SW620, Caco-2 human colorectal
cancer cells
MCF-7 breast cancer
MCF-7ras breast cancerMCF-7ras breast cancer
NSCLC A-549 human lung cancer
MCF-7 breast cancer
HL-60 human leukemia
3
22
50100
1001000
400800
72 h
24 h
24 h
72 h
72 h
N61
b61
510 (mM)
N62
b62
20
8d
8d
72 h
8d
8d
12 h
583722
N10 (g/ml)
N10 (g/ml)
N200
2550 (g/ml)
24 h
8d
8d
48 h
96 h
Thiacremonone SW620 and HCT116 human colon cancer cells

AGE
MCF-7 breast cancer
Garlic extract
NCI H460 and NCI1299 Non small cell lung cancer
Garlic oil
HL-60 human leukemia
Apoptosis
Apoptosis and G1 phase arrest Tubulin polymerization
Proliferation COX-2
Apoptosis Bcl-2
Cell growth ; G2/M arrest Cell growth ; G2/M arrest
Cell growth ; B(a)P-induced phase-1
Apoptosis, Caspase 3 and PARP1
Anchorage-dependent cell growth

Proliferation and Akt/mTOR/NF-kB
Proliferation ; G2/M arrest and proteasome
Proliferation ; G2/M arrest and proteasome
Apoptosis, NF-kB and Caspase-3
Apoptosis, p53 and Bax ; Bcl-2
Proliferation
Elango et al., 2004

Hong et al., 2000
Hosono et al., 2005
Xiao et al., 2004

Elango et al., 2004
Filomeni et al., 2003
Robert et al., 2001
Hong et al., 2000

Wu et al., 2011
Chandra-Kuntal &
Singh, 2010
Li et al., 2006
Hosono et al., 2005
Elango et al., 2004

Xiao et al., 2004
Wu et al., 2005
Chun et al., 2001
Liang et al., 2011
Pinto & Rivlin, 2001

Tang et al., 2010
Xu et al., 2004
Ban et al., 2007
Hong et al., 2000
Seki et al., 2000
DAS, diallyl sulde; DADS, diallyl disulde; DATS, diallyl trisulde; S-allyl mercaptocysteine; SAC, S-allylycysteine; AGE, aged garlic extract.
Decrease; , Increase.
its potential antitumor action (Xu et al., 2004). As a possible mechanism

of this inhibition, it has been suggested that allyl suldes may act to
increase activity of glutathione S-transferase (GST), which catalyzes
conjugation of electrophilic compounds with GSH (Sparnins et al.,
1986; Sparnins et al., 1988). The effect of these volatile substances
on (CYP1A1, 1A2 and 1B1)-mediated bioactivation of B(a)P was investigated using a human hepatoma cell model (HepG2). The cell viability,
an indicator of the capacity to inhibit B(a)P bioactivation, was increased
by treatments of 1001000 M DADS and 10100 M DATS. In addition,
DATS induced apoptosis of human BGC823 gastric cancer cells (Li et al.,
2006) and human HEK 293T keratinocytes (Elango et al., 2004). SAMC
(S-allylmercaptocysteine), the garlic-derived compound DADS induced
apoptosis through induction of active caspase-3 and PARP1 in human
SW480, SW620 and Caco-2 colorectal cancer cells (Liang et al., 2011).
DAS and DADS inhibited arylamine N-acetyltransferase activity
and 2-aminouorene (2-AF)-DNA adduct formation in HL-60 cell
line. This was the rst report of garlic components affecting human
leukemia cell NAT activity and 2-AAF-DNA adduct formation (Lin
et al., 2002). Thiacremonone, a novel recently identied organosulfur
compound from garlic, induced apoptotic cell death and increased
susceptibility of cancer cells with the combination of chemotherapeutic

agents. Treatment of thiacremonone inhibited colon cancer cell
growth, followed by induction of apoptosis, as well as suppression of
NF-B target anti-apoptotic genes (Bcl-2, cIAP1/2, and XIAP) and inammatory genes (iNOS and COX-2), whereas it induced apoptotic
gene (Bax, cleaved caspse-3, and cleaved PARP) expression (Ban et al.,
2007; Ban et al., 2009a). Moreover, oral treatment of mice with
thiacremonone (1 mg/kg) by administering it in drinking water for
4 weeks signicantly augmented docetaxel (1 mg/kg, i.p., four times)induced decrease of tumor growth accompanied with regulation
of NF-B activity and NF-B target genes. In the molecular docking
experiment, NF-B and thiacremonone exhibited binding afnity of
5.8 kcal/mol, and the binding pocket for thiacremonone was formed
by two beta-sheet peptide segments (Arg356, and Val412, Leu437
Leu440) and a loop (Gly361Gly365) in close proximity to the DNA
binding site of NF-B. Essentially, thiacremonone was shown to form
two and three hydrogen bonds with the surrounding amino acids.
Among these, one hydrogen bond interaction (between C1_O and
NH of Val412) was conserved (unpublished data). These results suggest
that induction of apoptosis and inhibition of NF-B by thiacremonone
188
Table 5
Cholesterol lowering effect of garlic in human.
Preparation
Doses
Duration
Effect
References
Tablet Garlic (KWAI)

Allicor (NAT-Farma, Moscow, Russia)
Allicor (NAT-Farma, Moscow, Russia)
Garlic powder tablet
Tablet garlic (Garlex-Bosch Pharmaceuticals)
Aged Kyolic garlic
Garlic tablet (Garlet)
AGE capsule
900 mg/d
300 mg/d
600 mg/d
800 mg/d
600 mg/d
2.4 g/d
920 mg/d (alliin 43.2 mg/d)
800 mg/d
880 mg/d
7200 mg/d
24 w
12 m
12 w
6w
12 w
2w
2w
3m
12 w
5m
TC, TG and LDL ; HDL

TC, TG and LDL
TC and LDL ; HDL
TC and TG ; LDL and HDL
TC and LDL ; TG and HDL
TC, TG, LDL and HDL
Ashraf et al., 2011

Sobenin et al., 2010
Kojuri et al., 2007
Ashraf et al., 2005
Williams et al., 2005
Turner et al., 2004
Ziaei et al., 2001
Kannar et al., 2001
Yeh & Liu, 2001
TC, Total Cholesterol; TG, Triglycerides; LDL, Low-density lipoproteins; HDL, High-density lipoproteins.
Decrease; , Increase.
could provide a specic and causative mechanism for the inhibition of

cancer cell growth, as well as provide novel evidences for combination
of chemotherapeutic agents with thiacremonone. Taken together,
organosulfur compounds isolated from garlic could exert great benecial effects due to its relatively low toxicity and better anti-cancer activities against different types of cancers with various action mechanisms.
Therefore organosulfur compounds could be potentially useful as chemotherapeutic agents for the treatment of cancers.
Garlic extract reduced cholesterol synthesis by up to 75% without

evidence of cellular toxicity. These results indicate that compounds containing an allyl-disulde or allyl-sulfhydryl group are most likely responsible for the inhibition of cholesterol synthesis by garlic and that
this inhibition is likely mediated at sterol 4 alpha-methyl oxidase. It
has also been shown that the more water-soluble compounds like SAC
present in aged garlic extract are less cytotoxic and more efcient in
inhibiting cholesterol biosynthesis than the lipid-soluble organosulfur
compounds such as DAS (Yeh & Liu, 2001).
4. Pharmaceutical effect of garlic on cardiovascular disorders

4.2. Effect of garlic on blood pressure
Numerous studies have conrmed the ability of garlic to reduce parameters associated with cardiovascular disease. A brief description of
some of these studies is given below.
4.1. Effect of garlic on cholesterol
Experimental evidence indicates that garlic ingestion lowers blood
cholesterol levels and inhibits cholesterol synthesis (Table 5). Zeng
and his colleagues deduced from 26 studies that hypercholesterolemic
patients treated with garlic (garlic powder and aged garlic extract)
had a mean serum TC and TG concentration, that were 0.28 (95%
CI, 0.45, 0.11) mmol/l (P = 0.001) and 0.13 (95% CI, 0.20,
0.06) mmol/l (P b 0.001) lower than that of patients treated with placebo, respectively (Zeng et al., 2012). Several experimental studies have
indicated that garlic and its constituents inhibit key enzymes involved
in cholesterol and fatty acid synthesis in cultured rat hepatocytes and
human HepG2 cells (Gebhardt, 1993; Yeh & Yeh, 1994; Liu & Yeh,
2001; Yeh & Liu, 2001). Cultured hepatoma cells were treated with
aqueous garlic extract and radiolabeled cholesterol was quantied.
In patients with uncontrolled hypertension (SBP N/= 140 mm Hg at

baseline), systolic blood pressure was on average 10.2 +/ 4.3 mm Hg
(P = 0.03) lower in the garlic group who consumed four capsules of
aged garlic extract (960 mg containing 2.4 mg SAC) daily for 12 weeks
compared with controls over the 12-week treatment period (Ried
et al., 2010). Garlic reduces blood pressure (BP) in two-kidney, oneclip (2K-1C) rats through enhancement of nitric oxide (NO) synthesis
in in vivo and in vitro as well as in human (Sobenin et al., 2008;
Qidwai et al., 2000; Ried et al., 2010) (Table 6). Garlic appears to exert
this effect by modulating the activity of several mechanisms that are
vital in BP homeostasis in favor of hypotension. One possible mechanism
by which garlic might induce its hypotensive effect could be through
the direct and indirect vasodilatory actions of NO. The drinking
water was replaced with an L-Arg solution (10 mg/ml; average intake
of 300 mg/day) from 7 to 14 days. A day after surgery, there was a signicant reduction of mean blood pressure in the L-Arg-treated group
compared to control (129 7 vs 168 6 mm Hg) (Kim-Park & Ku,
2000; Gouvea et al., 2003). Morihara et al. (2002) also reported that
Table 6
Blood pressure effect of garlic in human.
Preparation
Doses
AGE
Allicor (coated tablets containing 150 mg garlic powder,
INAT-Farma, Moscow, Russia)
Garlicin tablet (produced by Xinjiang Tianshan Pharmaceutical Factory)
AGE Kyolic
Clove of garlic
Dried garlic powder tablets (Futura Hvidlg Fortew; Dansk Droge,
Ishj, Denmark)
Garlic pearls (GP; Ranbaxy Laboratories Ltd., Mumbai, India).
Aqueous garlic extract (20%, w/v) (Kastamonu garlic).
Garlic tablet
Garlic oil
Garlic tablet Garlet
Garlic powder
Garlic tablet (Garlet)
Garlic
Kwai garlic tablets
960 mg/d (2.4 mg S-allylcysteine) 12 w

600 mg/d
12 w
SBP ; DBP
SBP ; DBP
Ried et al., 2010

24 mg/d
3 g/d (S-allylcysteine 14 mg)
1 g/d
920 mg/d (alliin 108 mg)
4w
20 m
2m
12 w
SBP ; DBP
SBP ; DBP
SBP ; DBP
No signicance
Cheng et al., 2006

Macan et al., 2006
Jabbari et al., 2005
Turner et al., 2004
250 mg/d
10 g/d
1 g/d (1.5 mg allicin)
12.3 mg/d
800 mg/d (1 mg allicin, ajoene)
1200 mg/d (1 mg Allicin)
800 mg/d
134 g/m
900 mg/d
8w
4m
12 w
16 w
8w
4w
3m
1m
12 w
SBP ; DBP
Hypertention
No signicance
SBP
SBP and DBP ; Hypertention
SBP ; DBP
Hypertention
SBP ; DBP
No signicance
Dhawan & Jain, 2004

Durak et al., 2004
Gardner et al., 2001
Zhang et al., 2001
Ziaei et al., 2001
Mortazavi et al., 2001
Ziaei et al., 2001
Qidwai et al., 2000
Superko & Krauss, 2000
SBP, systolic blood pressure; DBP, diastolic blood pressure; , Decrease; , Increase.
Duration effect
References
extract of garlic (2.86 g/kg) increased NO production by 3040% from 15

to 60 min after administration (Morihara et al., 2002). Elevating evidence indicates that hydrogen sulde (H2S) plays a cell signaling role
similar to NO and CO. In vivo and in vitro cardiovascular effects of H2S
include decreased blood pressure and cardioprotection against ischemic
damage and vasorelaxation (Zhao et al., 2001; Sivarajah et al., 2006;
Koenitzer et al., 2007). A recent study by Benavides et al. suggests that
H2S may underlie the benecial effects that garlic exerts on the cardiovascular system (Benavides et al., 2007). Garlic and garlic-derived organic polysuldes, including DATS and DADS induced H2S production
in a thiol-dependent manner (Calvert et al., 2010). Garlic-mediated
and H2S-mediated vascular smooth muscle relaxation indicate that
both were based on NO signaling pathways (Benavides et al., 2007).
4.3. Effects of garlic on platelet aggregation

Like cholesterol and blood pressure lowering effects, garlic also has a
benecial effect on platelet aggregation in human as well as in animal
(Table 7). Platelet aggregation and subsequent thrombus formation
are signicantly reduced by garlic and its constituents. All constituents
displayed a biphasic pattern of inhibition that was only signicant for
SEC at 0.78 mol/l, SMC at 3.125 and 6.25 mol/l, SPC at 0.78, 3.125
and 6.25 mol/l, and BC at 0.78, 3.125 and 25 mol/l. Aqueous garlic extracts (nal concentration, 1 mg/ml) inhibited human platelet aggregation (Pierre et al., 2005). DATS inhibited platelet aggregation and
Ca(2+) mobilization in a concentration-dependent manner without increasing intracellular cyclic AMP and cyclic GMP. DT at high concentrations partially blocked the binding of IP(3) to its receptor (Qi et al.,
2000). The mechanism of inhibition of platelet aggregation by garlic's
constituents has also been addressed, and it is thought to work via the
inhibition of calcium mobilization (Qi et al., 2000). A recent study has
also found another garlic component, sodium 2-propenyl thiosulfate,
to modulate cyclooxygenase activity in canine platelets, thus preventing
their aggregation (Chang et al., 2005). Overall, there are sufcient evidences in terms of reducing the risk of cardiovascular diseases and it
suggests that organosulfur compounds could be potentially developed
into a health product for the cardiovascular system.
Table 7
Anti-platelet aggregatory effect of garlic in human.
Preparation
Doses and
concentrations
Duration
Garlic tablet
225 mg/d
5 y & 9 m PA
Garlic oil
9.9 g/d
4h
AGE
AGE
7.2 g/d
5 ml/d
6w
13 w
SEC
(In vitro) 0.78 M
5 min
SMC
(In vitro) 3.1256.25 M 5 min
SPC
(In vitro) 0.786.25 M
5 min
BC
(In vitro) 0.7825 M
5 min
AGE
(In vitro) 80 mg/ml
10 min
Aqueous garlic (In vitro)1 mg/ml

extracts
Diallyl
(In vitro) 10 g/ml
trisulde
15 min
5 min
Effect
References
Manoharan
et al., 2006
No
Wojcikowski
signicance et al., 2007
PA
Steiner & Li, 2001
PA
Rahman &
Billington, 2000
PA
Allison et al.,
2006a
PA
Allison et al.,
2006a
PA
Allison et al.,
2006a
PA
Allison et al.,
2006a
PA
Allison et al.,
2006b
PA
Pierre et al.,
2005
PA
Qi et al., 2000
SEC, S-ethylcysteine; SMC, methyl-L-cysteine; SPC, S-1-proponyl-L -cysteine; BC,

-chlorogenin.
PA, Platelet aggregation, : Decrease
189
5. Pharmaceutical effect of garlic on neurological diseases

Recent studies have demonstrated benecial effects of AGE and one
of its active ingredients SAC in Alzheimer disease models (Chauhan,
2006; Ray et al., 2011a,b) (Table 8). The therapeutic effects of SAC
were also assessed in various models of neurodegenerative diseases including stroke (Kim et al., 2006; Atif et al., 2009), ischemia/reperfusion
(Ashafaq et al., 2012), Alzheimer's disease (Perez-Severiano et al., 2004;
Javed et al., 2011), and Parkinson's disease (Garcia et al., 2010). The molecular mechanisms of these effects may include protecting neurons
against oxidative/nitrosative (reactive oxygen/nitrogen species) stress,
mitochondrial damage, and subsequent cell death. SAC also reduces
edema formation in the ischemic rat brain through the inhibition
of LPO (Numagami et al., 1996) and produces neuroprotective effects
on the A-induced oxidative damage, and learning decits (PerezSeveriano et al., 2004).
Thiacremonone also inhibited LPS-induced memory impairment, glial
activation, pro-inammatory mediator expression, and amyloidogenesis
in in vitro and in vivo via the inactivation of NF-B via blocking of
phosphorylation of IB in mice brain as well as cultured astrocytes
and microglial BV-2 cells (Lin et al., 2012). These results indicated that
thiacremonone inhibited neuroinammation and amyloidogenesis
through inhibition of NF-B activity, which controls the genes involved in not only inammation but also amyloidogenesis. Therefore,
organosulfur compound in garlic could be applied for intervention of
inammation-related neurodegenerative disease including Alzheimer's
disease, stroke, and Parkinson's disease.
6. Other pharmaceutical effects of garlic
6.1. Pharmaceutical effect of garlic on liver diseases
Recent human study suggests that garlic offers protection against
oxidative stress and antioxidant activities in alcoholic liver disease patients (Table 9). Preclinical studies have shown that garlic ameliorates
alcohol-induced oxidative stress (Zeng et al., 2008; Nencini et al.,
2010), inhibits induction of cytochrome P450 (CYP) (Kishimoto et al.,
1999) and prevents fatty liver and liver cirrhosis (Zeng et al., 2008).
Garlic is also shown to reduce the ethanol-induced increase in the
lipid peroxidation and to increase the levels of antioxidants such
as glutathione (GSH), ascorbic acid, catatase (CAT), and glutathione
reductase (GR) in the rat liver (Nencini et al., 2010). Garlic and its
organosulfur components have been shown to increase the activity of
GSH-related antioxidant system in rat liver (Wu et al., 2001), and
have been demonstrated to provide protective effects against oxidative
stress by chemicals (Yang et al., 2001; Khosla et al., 2004; Park et al.,
2005; Agarwal et al., 2007). Treatment of SAMC attenuated nonalcoholic fatty liver disease (NAFLD)-induced liver injury, fat accumulation, collagen formation and free fatty acids through reduction
of MAP kinase pathways and the NF-B and AP-1 activity (Xiao
et al., 2013).
One of the major protective functions of garlic is to decrease the oxidative damage in liver (Gedik et al., 2005). Indeed, garlic prevents the
infection induced loss of GSH and decrease of activities of catalase and
SOD. These components are normally lowered during oxidative damage
induced by infection as it has been also described by Georgieva et al.
(2006) who showed an increase in malondialdehyde (MDA) levels of
Eimeria tenella-induced coccidiosis. In accordance, Kiruthiga et al.
(2007) have found that garlic signicantly decreased lipid peroxidation
and increased GSH, catalase and SOD. The antioxidative property of garlic has been previously ascribed mainly to its four major chemical components, i.e. allinin, SAC, DADS, and allicin (Chung, 2006). In addition,
Raso et al. (2001) have viewed that the oxidative stress is mainly due
to NO produced by the stimulated iNOS. The inhibitory effect of garlic
is mainly attributed to the impaired action of iNOS (Gu et al., 2003;
Chang & Chen, 2005). Our data also showed that thiacremonone
190
Table 8
Effect on neurological diseases of garlic.
Components
Diseases
Doses
Duration
Effects
References
DADS
SAC
SAC
Thiacremonone
SAC
DAS
AGE
SAC
Alzheimer's diseases
Ischemia
Ischemia
Ischemia
Parkinson's diseases
20 mg/kg
20 mg/kg
30 mg/kg
1, 3, and 10 mg/kg
300 mg/kg
100, 150, and 200 mg/kg
1.2 ml/kg
120 mg/kg
4 months
4 months
15 days
1 month
30 min before MCAO
7 days before MCAO
30 min before MCAO
5 days
Anti-amyloidogenic, anti-inammatory and anti-tangle effects

Anti-amyloidogenic, anti-inammatory and anti-tangle effects
Cognitive and neurobehavioral improvement
Memory improvement, glial inactivation, and anti-amyloidogenesis
Reduction of infarct size
Increase in Bcl-2 and decrease in caspase-3
Reduction of SOD, GPX, and EC-SOD activities
Reduction of TNF-, iNOS, and GFAP expression
Chauhan, 2006
Chauhan, 2006
Javed et al., 2011
Lin et al., 2012
Kim et al., 2006
Lin et al., 2012
Aguilera et al., 2010
Garcia et al., 2010
MCAO, Middle cerebral artery occlusion; GPX, Glutathione peroxidase; SOD, Superoxide dismutase; EC-SOD, Extracellular superoxide dismutase.
reduced acute hepatic injury through inactivation of NF-B and STAT3

by inhibition of pro-inammatory cytokine production (unpublished
data). Taken together, all these observations indicate the usefulness of
garlic in the prevention of liver diseases.
cells and chondrocytes (Lee et al., 2009). A 110 mg/kg dose of

thiacremonone also suppressed the carrageenan and mycobacterium
butyricum-induced inammatory and arthritic responses as well as expression of iNOS and COX-2, in addition to NF-B DNA-binding activity
(Ban et al., 2009a).
6.2. Pharmaceutical effect of garlic on allergy

7. Pharmacokinetics
Several studies suggested anti-allergic properties for garlic extract
(Table 9). Kyo et al. (2001) reported that in their rodent basophile
cell line model, addition of garlic extract reduced histamine release
(anti-histamine effect). They showed suppression of IgE-mediated
antigen-specic skin reaction in murine model too and concluded
that garlic extract could benecially balance, or modify the function
of mast cells, basophile, and activated T lymphocyte factors, which
all play a leading role in allergic cascade reactions and inammation.
Three-time intra peritoneal injections of the aged garlic extract caused
a signicant decrease in the hallmark criteria of allergic airway inammation levels which included eosinophil percentage in lavage,
peribronchial lung eosinophils, IgG1 level in lavage and serum, mucous producing goblet cell grade and peribronchial and perivascular
inammation (Zare et al., 2008). Aged red garlic extract reduces cigarette smoke extract-induced cell death by increasing GSH content and
reducing ROS generation in human bronchial smooth muscle cells
(Jeong et al., 2012).
6.3. Pharmaceutical effect of garlic on arthritis
Several studies have also shown that garlic extract is helpful at
preventing arthritis (Table 9). Consumption of alliums (garlic, leeks,
and onions) (P = 0.029) showed the strongest protective association
with hip osteoarthritis (OA) (Williams et al., 2010). They suggested
that diallyl disulde, a compound found in garlic and other alliums, represses the expression of matrix-degrading proteases in chondrocytelike cells, providing a potential mechanism of action (Williams et al.,
2010). DAS (48.9 mg/kg) signicantly inhibited the increase of IL-1
generation and COX-2 gene expression through inactivation of NF-B
induced by monosodium urate crystals in a rat model and in synovial
There have been many reports on the pharmacokinetics of garlic and

its constituents. The oil-soluble organosulfur compounds in garlic,
including allicin, ajoene, and vinyldithiins are not found in blood or
urine, even after consumption of a large amount of garlic (Lawson
et al., 1992). Therefore, they are likely not the active compounds. Allicin,
perfused into isolated rat livers, showed a remarkable rst-pass effect
and is metabolized to DADS and allyl mercaptan, whereas ajoenes and
vinyldithiins were recovered in the efuent (Egen-Schwind et al.,
1992a,b). Allicin disappeared very rapidly when incubated with liver
homogenate (Egen-Schwind et al., 1992a,b). No allicin was detected in
either serum or urine from 1 to 24 h after ingestion of 25 g of raw garlic
(90 mg allicin) (Lawson et al., 1992). DADS is a metabolite of allicin
(Egen-Schwind et al., 1992a,b). The maximum concentration of
radiolabeled DADS in the liver of mice occurred 90 min after intraperitoneal administration (Pushpendran et al., 1980). Seventy percent of
the radioactivity, which was no longer DADS, was distributed in the
liver cytosol, of which 80% was metabolized to sulfate. DADS, like allicin,
was not detected in human blood or urine from 1 to 24 h after oral
ingestion of 25 g of crushed raw garlic (Lawson et al., 1992). The instability and/or metabolism of such compounds likely contributes to the
inconsistent results found in the clinical cholesterol studies using garlic
oil (Berthold et al., 1998) and garlic powder products (Simons et al.,
1995; Neil et al., 1996; Breithaupt-Grogler et al., 1997; Berthold et al.,
1998; Isaacsohn et al., 1998; McCrindle et al., 1998). Metabolites
of garlic constituents, such as N-acetyl-S-(2-carboxypropyl)-cysteine,
N-acetylcysteine, and hexahydrohippuric acid have been detected in
human urine after ingestion of garlic (Jandke & Spiteller, 1987). After
consumption of garlic, N-acetyl-S-allyl-cysteine is found in human
urine. At present, SAC is the only reliable human compliance marker
Table 9
Other pharmaceutical effects of garlic.
Components
Diseases
Doses and concentrations Duration
Effects
References
Raw garlic cloves

Garlic extracts
Garlic oil
SAMC
Aqueous garlic extract
Aged garlic extract
Garlic extract
DADS
DAS
Thiacremonone
Liver diseases
Liver diseases
Liver diseases
Liver diseases
Liver diseases
Allergy
Allergy
Arthritis
Arthritis
Arthritis
2 cloves/body (2.4 g)
250 mg/kg
200 mg/kg
200 mg/kg
250 mg/kg
250 mg/kg
20 mg/kg
2.510 M
48.9 mg/kg
10 mg/kg
Oxidative stress and antioxidant activities

Oxidative stress, GR and CAT activities
Decrease in oxidation process
Reduction of MAPK, NF-B, AP-1, and cytochrome P450 2E1 activity
Reduction of GSH, CAT, and SOD activities
Decreased 2545% of the ear swelling
Decreased allergic airway inammation levels
Protective effects in hip osteoarthritis
Decrease in IL-1 and COX-2
Inhibition of the carrageenan paw edema
Mirunalini et al., 2010

Nencini et al., 2010
El-Khayat et al., 2010
Xiao et al., 2013
Gedik et al., 2005
Kyo et al., 2001
Zare et al., 2008
Williams et al., 2010
Lee et al., 2009
Ban et al., 2009b
45 days
5 days
15 days
Three times/week
28 days
24 h
48 h
6h
24 h
20 days
GR, Glutathione reductase; GSH, Glutathione; CAT, Catalase; SOD, Superoxide dismutase.
used for studies involving garlic consumption because it is detectable

and increases quantitatively in the blood after oral intake of garlic
capsules (Steiner & Li, 2001). The pharmacokinetic studies of SAC demonstrated rapid absorption and almost 100% bioavailability after oral administration. The absorbed SAC seems to be metabolized to N-acetylSAC in urine of rats, dogs, and humans by N-acetyltransferase, which
is mainly found in liver and kidney. However, it has been shown that,
when SAC is almost completely eliminated from the liver, it is readily
retained at a comparatively high concentration in the kidney. Thus, it
can be speculated that SAC may be transformed into N-acetyl-SAC by
N-acetyltransferase in the liver, and then, a portion of N-acetyl-SAC
may be deacylated to SAC by acylase in kidney, followed by its reabsorption. In addition, since both the safety and effectiveness of SAC have
been reported, this compound appears to play an important role in
garlic's medicinal effects. Though individual compounds such as SAC
have shown activity in studies and are absorbed by the body, it is likely
that a synergism of various compounds provides the benets of garlic.
Thus, the activity of various sulfur compounds could not alone be
responsible for the benets of garlic, and xation on a single group of
components can lead to mistakes and wrong conclusions. Overall, the
active principles in garlic have not been fully characterized. However,
it is assumed that the bioavailability of these sulfur-containing compounds will play an important role in determining the biological response to various garlic preparations.
8. Toxicity and safety
Although garlic has been used safely in cooking as a popular condiment or avoring and used traditionally for medicinal purposes, it is
commonly known that excessive consumption of garlic can cause problems. Adverse effects that have been documented in humans include a
burning sensation in the mouth and gastrointestinal tract, nausea, diarrhea, vomiting (Fulder, 1989; Barnes et al., 2007) and body odor. The
allergenic potential of garlic is well recognized, and the allergens have
been identied as DADS, allylpropyl sulde and allicin (Papageorgiou
et al., 1983; Barnes et al., 2007). Since 1932, several reports have
revealed the following adverse effects associated with raw garlic and
garlic powder: 1) stomach disorders and diarrhea (Nakagawa et al.,
1980; Caporaso et al., 1983; Desai et al., 1990); 2) decrease of serum
protein and calcium (Miyamoto, 1938; Shashikanth et al., 1986); 3) anemia (Katsunuma, 1932; Kuzutani, 1934; Nakagawa et al., 1980);
4) bronchial asthma (Lybarger et al., 1982; von Kirsten & Meister,
1985); 5) contact dermatitis (Mitchell, 1980; Parish et al., 1987;
Lembo et al., 1991; McFadden et al., 1992; Garty, 1993; Burden et al.,
1994); and 6) inhibition of spermatogenesis (Dixit & Joshi, 1982; Qian
et al., 1986). Allicin can be an oxidizing agent that not only impedes bacterial growth (Shashikanth et al., 1986) but also can damage the intestinal lining and the stomach (Kodera, 1997). Raw garlic juice (0.5 ml)
caused signicant damage to the epithelial mucosal membrane after
191
2 h in rats. Enteric-coated garlic products are designed to deliver allicin

(15 mg, depending on the product label claim) directly into the intestinal tract. After 24 h of exposure, ulcers, shrinkage, and bleeding in the
epithelial mucosa were detected. When three kinds of commercially
available enteric-coated garlic preparations, i.e., Garlicin, Garlique, and
Garlinase 4000, were used at dosages of 133, 108 and 60.5 mg/rat, respectively, each caused severe damage to the duodenal mucosa after
2 h of exposure (Amagase et al., 2001). According to their study,
enteric-coated garlic powder products, which are designed to generate
allicin in the delicate intestine, may be hazardous to the intestinal tract
(Amagase et al., 2001).
On the other hand, a number of toxicological and clinical studies of
garlic extracts have been performed with no adverse effects. The safety
of garlic extracts has been well established by the following studies
(Table 10): 1) acute and subacute toxicity tests (Nakagawa et al.,
1984a,b); 2) chronic toxicity test (Sumiyoshi et al., 1984); 3) mutagenicity tests (Yoshida et al., 1984); 4) general toxicity tests (Nakagawa
et al., 1980; Kanezawa et al., 1984); 5) teratogenicity tests (Segments
I, II, and III) (Assayed et al., 2010); 6) toxicity test conducted by the
U.S. Food and Drug Administration; and 7) clinical studies conducted
on N1000 subjects (Hasegawa et al., 1983; Kawashima et al., 1989;
Steiner et al., 1996). The United States National Cancer Institute tested
toxicity of typical garlic compounds. In humans, daily doses of up to
60 g of fresh garlic and 120 mg of essential oil of garlic, over a period
of three months, did not result in any serious disorders (Anonymous,
1997). Recent clinical trials report garlic extracts to be safe as a complementary medicine with warfarin (Macan et al., 2006). Such characteristics may come from the AGE processing method and clearly differentiate
the extract from other preparations. SAC is a safe compound and its
biological effects are well studied. The U.S. National Cancer Institute
(NCI) investigated the toxicity of SAC when compared with other garlic
compounds and found that SAC has less toxicity than allicin and DADS.
The oral 50% lethal dose in mice is as follows for allicin: 309 mg/kg
in males and 363 mg/kg in females; for DADS: 145 mg/kg in males
and 130 mg/kg in females; and for SAC: 8890 mg/kg in males and
9390 mg/kg in females (Amagase, 2006).
9. Perspective
In vitro and in vivo as well as clinical trials have demonstrated that
garlic may be an important traditional medicine to treat a variety of
conditions such as cancer, cardiovascular disease, neurological disease,
and liver disease as well as allergy and arthritis. Garlic contains at least
alliin, -glutamyl-S-allylcysteine, S-methylcysteine sulfoxide, S-trans1-propenylcysteine sulfoxide, S-2-carboxypropylglutathione, SAC, and
thiacremonone, which have a wide variety of pharmaceutical properties. Recent study demonstrated that garlic (Allicin) had selectivity
on the sulfonylurea receptors (SURs) (Harikesh et al., 2012). SURs
are membrane proteins which are the molecular targets of the
Table 10
Toxicological properties of garlic extracts.
Tests
Preparation
Doses and
concentrations
Administration
Duration
effects
Model
References
Acute toxicity
Chronic toxicity
Garlic extract
Garlic extract
30 mg/kg
602000 mg/kg
P.P., I.P., S.C.

Oral
7 days
6 months
Wistar rat, dYY mouse

Wistar rat
Nakagawa et al., 1984b

Sumiyoshi et al., 1984
Mutagenicity
1002500 mg/kg
Oral
18 days
Mouse, Chinese hamster
Yoshida et al., 1984
0.0121.2 mg/ml
In vitro
7 days
Yoshida et al., 1984
5 ml/kg
Oral
5 days
Wistar rat
Kanezawa et al., 1984
275.5 mg/kg
Oral
5 days/week
Wistar rat
Assayed et al., 2010
Clinical study
Garlic extract
7.2 g/day
Diet
6 months
Growth inhibition and morphological

change
Stomach injury, weight loss, swelling of
various organs
Prevention of cypermethrin-induced
teratogenic effects.
Reduction in cholesterol, blood pressure
CHE cell, HEp-2 cell line
Teratogenicity
Garlic extract
vs raw garlic
Garlic extract
vs raw garlic
Garlic extract
vs raw garlic
Garlic extract
No effect (LD50 N 30 mg/kg)

No weight gain and toxic sign, slightly
decreased food consumption
Increase of MNC and PC
Men (3268 age group)
Steiner et al., 1996
Cytotoxicity
General toxicity
MNC, Micronucleated cell; PC, Polychromatocytes; CHE, Chinese hamster embryo.
192
sulfonylurea class of antidiabetic drugs whose mechanism of action is

to promote insulin release from pancreatic beta cells. More specically,
SUR proteins are subunits of the inward-rectier potassium ion channels Kir6.x (Campbell et al., 2003). Four Kir6.x and four SUR subunits
compose an ion conducting channel referred to as the KATP channel
(Aguilar-Bryan et al., 1998). Garlic extract exhibited anti-diabetic and
anti-hypertensive effects as a vasodilator by hyperpolarizing the membrane of normal vascular smooth muscle cells. The hyperpolarization
in vascular smooth muscle was induced due to K+ channel opener activity. Anti-hypertensive activity of garlic extract was suppressed by
glibenclamide (nonselective SUR blocker) whereas nateglinide (selective SUR1 blocker) exhibited antihypertensive effect with garlic extract
(Harikesh et al., 2012). These studies validated that garlic will be effective in the treatment of hypertensive diabetes. Garlic also showed
antihypertensive activity by selective opening of SUR2. Under cerebral
ischemic conditions SUR1 (the regulatory subunit of the KATP- and the
NCCa-ATP-channels) is expressed in neurons, astrocytes, and microglia
(Simard et al., 2012). SUR1 is involved in animal stroke through
preventing brain swelling and enhancing neuroprotection (Ortega
et al., 2012). Garlic-derived organic polysuldes also induced H2S production (Benavides et al., 2007). H2S is the rst identied endogenous
gaseous opener of ATP-sensitive K+ channels in vascular smooth muscle cells (Zhao et al., 2001). H2S lowers blood pressure, protects the
heart from ischemia and reperfusion injury, inhibits insulin secretion
in pancreatic beta cells, and exerts anti-inammatory, anti-nociceptive
and anti-apoptotic effects through the activation of ATP-sensitive K+
channels (Tang et al., 2010).
Thus, functionally active components isolated from garlic have
benecial effects in a variety of diseases and will have a wide range of
applications. We suggest that this review will shed light on a foundation
for further studies to investigate mechanisms underlying the effects
of functionally active components isolated from garlic, and clinical
applications of these components.
Conict of interest
The authors declare that there are no conicts of interest.
Acknowledgments
This work was supported by the National Research Foundation of
Korea (NRF) grant funded by the Korean Government (MISP) (No.
MRC, 2008-0062275), by a grant (A101836) from the Korean Health
Technology R&D Project, Ministry for Health, Welfare and Family Affairs,
Republic of Korea.
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Potential Therapeutic Effects of Funct

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Pharmacology & Therapeutics 142 (2014) 183195

Contents lists available at ScienceDirect

Pharmacology & Therapeutics

Associate editor: I. Kimura

Potential therapeutic effects of functionally active compounds isolated

Available online 11 December 2013

maintain and increase their strength, thereby enabling them to work

H.-M. Yun et al. / Pharmacology & Therapeutics 142 (2014) 183195

Kimbaris et al., 2006). Recently, a novel organosulfur compound,

effects, as well as effects for prevention of allergy and arthritis

Korean garlic cloves

Yoo et al., 2010

Yoo et al., 2010

Kimbaris et al., 2006

Kimbaris et al., 2006

Naznin et al., 2008

Amagase & Milner, 1993

Hwang et al., 2007

H.-M. Yun et al. / Pharmacology & Therapeutics 142 (2014) 183195

Thermidrome) (Bloem et al., 2011). Shimpo et al. (2002) found

2008). Soybean oil was composed of E-ajoene (172.0 g/g of garlic)

Pourfarzi et al., 2009

OR, odds ratios.

Kim et al., 2007

BALB/CAnN-Foxn1 nude mice Tang et al., 2010

Nishikawa et al., 2002

Apoptosis, caspase 3 and PARP1

Singh et al., 2008

BALB/c nude mice

Kalra et al., 2006

Apoptosis, p53 and p21; Bcl-2 and survivin

DMBA-induced skin carcinogenesis

Preclinical studies have provided convincing evidence that several

3.2. Anti-cancer effect of garlic in in vivo and in vitro studies

lower risk of gastric cancer than those who never or infrequently

inhibition Animal model

H.-M. Yun et al. / Pharmacology & Therapeutics 142 (2014) 183195

H.-M. Yun et al. / Pharmacology & Therapeutics 142 (2014) 183195

Cancer cell type

HCT-15 and DLD-1 human colon tumor cells

Hosono et al., 2005

HEK 293T keratinocytes

Apoptosis and G1 phase arrest ; Tubulin polymerization

HCT-15 and DLD-1 human colon tumor cells

PC3 prostate cancer

Apoptosis, intracellular ROS and G2/M cell cycle arrest

NCI H460 and NCI1299 Non small cell lung cancer b5

DU145 LNCaP human prostate cancer

Human BGC823 gastric cancer

Human HEK 293 T keratinocytes

Thiacremonone SW620 and HCT116 human colon cancer cells

Anchorage-dependent cell growth

Elango et al., 2004

Hosono et al., 2005

Xiao et al., 2004

Hong et al., 2000

Elango et al., 2004

Pinto & Rivlin, 2001

its potential antitumor action (Xu et al., 2004). As a possible mechanism

susceptibility of cancer cells with the combination of chemotherapeutic

H.-M. Yun et al. / Pharmacology & Therapeutics 142 (2014) 183195

Tablet Garlic (KWAI)

TC, TG and LDL ; HDL

Ashraf et al., 2011