International Journal of Food Properties

ISSN: 1094-2912 (Print) 1532-2386 (Online) Journal homepage: https://www.tandfonline.com/loi/ljfp20

Allicin and Other Functional Active Components in

Garlic: Health Benefits and Bioavailability

Mohammad Shafiur Rahman

To cite this article: Mohammad Shafiur Rahman (2007) Allicin and Other Functional Active
Components in Garlic: Health Benefits and Bioavailability, International Journal of Food Properties,
10:2, 245-268, DOI: 10.1080/10942910601113327

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International Journal of Food Properties, 10: 245–268, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1094-2912 print / 1532-2386 online
DOI: 10.1080/10942910601113327

ALLICIN AND OTHER FUNCTIONAL ACTIVE

COMPONENTS IN GARLIC: HEALTH BENEFITS
AND BIOAVAILABILITY

Mohammad Shafiur Rahman

Department of Food Science and Nutrition, College of Agricultural and Marine
Sciences, Sultan Qaboos University, Al-Khod, Sultanate of Oman

Traditionally, the medical properties of garlic were recognized as early as 3000 BC. The
functional benefits of garlic are its antimicrobial activity, anticancer activity, antioxidant
activity, ability to reduce cardiovascular diseases, improving immune functions, and anti-
diabetic activity. Recent studies identify the active functional components providing the
medicinal benefits, as well as their mechanisms of action including the best possible ways to
consume garlic. Allicin (diallyl-thiosulfinate) is one of the major organosulfur compounds
in garlic considered to be biologically active. In this article, I review the chemistry of allicin
and its stability during processing and storage, in-vivo and in-vitro functionality of allicin,
and other functional components. In addition, I explore other potential alternative
approaches of making its derivatives and their use for health benefits.

Keywords: Garlic, Allicin, Bioavailability, Functional component, Alliin.

INTRODUCTION
Garlic (Allium sativum L.), like other plants, has an exquisite defense system, composed
of as many different components as the human immune system. In order to protect itself from
insects and fungi, garlic produces allicin by enzymatic reaction when it is injured. Thus, allicin
is mother-nature’s insecticide. Since ancient times, garlic has been used worldwide, not only
as a food, but also as a medicine. As early as 3000 B.C., in ancient civilizations, including
Egyptian, Phoenicians, Greek, Indian, Roman, Babylonian, Viking, and Chinese, garlic was
used for treatment of heart conditions, arthritis, pulmonary complaints, abdominal growths
(particularly uterine), respiratory infections, skin disease, symptoms of aging, diarrhea, head-
ache, bites, worms, wounds, ulcers, and tumors.[1,2,3] The ancient Chinese consumed garlic to
achieve longevity. In the days of the Pharaohns, during the building of Great Pyramid of
Cheops at Gizeh, when the supplies of garlic ran out the work force withdrew their labor. They
knew well that garlic gave them strength and stamina. In the first century AD, Dioscorides, the
chief physician of Roman army, prescribed garlic to his warriors and wrote: garlic cleans the
arteries.[4] The use of garlic to treat wounds surfaced repeatedly through the middle ages into
World War II, when garlic was used to treat the wounds of soldiers.[5]

Received 10 May 2006; accepted 16 August 2006.

Address correspondence to Mohammad Shafiur Rahman, Department of Food Science and Nutrition,
Sultan Qaboos University, Muscat, Al-khod 123, Oman. E-mail: [email protected]

245
246 RAHMAN

Recently, other medical effects of garlic and certain constituents of garlic or other
transformed products have been studied. The biological responses include reduction of
risk factors for cardiovascular diseases and cancer, a stimulation of immune function,
enhanced foreign compound detoxification, radio protection, restoration of physical
strength, cholesterol-lowering, resistance to various stresses and potential anti-aging
effects.[6] Garlic consumption is correlated to reduced cancer risk, and its extracts and
components effectively blocked experimentally induced tumors in a variety of sites
including skin, breast, uterine cervix and colon, suggesting a general mechanism of
action.[7,8,9] Commercially available garlic supplements fall into 4 categories: dehydrated
garlic powder, garlic oil, garlic oil macerate, and aged garlic extract.[6] Aqueous garlic
extract might exert its chemo-preventive effect by inducing apoptosis,[10] cytotoxic to
HeLa, a human cervical cancer cell line.[11]
There is no standard available for intake of garlic.[6] The 1988 German Kommission
E monograph[6] proposed that daily intake of ∼1–2 cloves garlic or ∼4 g of intact garlic may
have health benefits. However, this recommendation was not substantiated with a
scientific reference. Amagase, Petesch, Matsuura, Kasuga, and Itakura[6] mentioned that in
many recent clinical studies, the daily dose of dehydrated garlic powder has been ∼900 mg.
Aged garlic extract intakes ranging from 1 to 7.2 g/day have been used with success. Studies
showing immune enhancement in human showed as little as 1.8 g to as much as 10 g/day
of age to be effective.[12,13,14] Interestingly, no severe toxic side effects were reported in
these clinical studies, even at high dosages.
Many organosulfur compounds, the major active principles in garlic, inhibited the
proliferation of cancer cells, and some of them induced apoptosis in tumor cells of different
tissue origin.[15,16,17,18,19] Allicin [S-(2-propenyl) 2-propene-1-sulfinothioate] is one of the
most widely known organosulfur compounds derived from garlic. The objectives of this
review is to present the present knowledge on the chemistry of allicin and other organo-
sulfer compounds and their stability during processing and storage, in-vivo and in-vitro
functionality, and other potential alternative approaches of making its derivatives.

CHEMISTRY OF ALLICIN AND ITS STABILITY

The pioneering studies of Semmler[20] established the importance of diallyl disulfide
and diallyl trisulfide in the flavor of garlic distillates. Allicin (diallyl-thiosulfinate) is the
most biologically active compound of garlic. Allicin was discovered in 1944 by Cavallito
and Bailey[21] and then Cavallito et al.[22] first noted its potent antimicrobial activity. The
structure of allicin is shown in Figure 1A. Allicin is not present in raw garlic, but it is rap-
idly produced by the action of CS-lyase (allinase) on alliin. The structure of alliin is shown
in Fig. 1B. Allinase is activated by crushing or cutting the garlic cloves.[1,21,22,23] Allicin
represents about 70% of the overall thiosulfinates present in the cloves upon mechanical
crushing.[24,25,26] Mechanistic and pharmacokinetic studies of allicin and its derivatives
raise the need for a labeled compound. Labeling of this volatile and unstable liquid
requires delicate handling. Miron et al.[28] described a simple method for the preparation
of 3H-labeled allicin.
The main sulfur compound in both raw garlic and garlic powder is alliin. On average,
garlic cloves contain ∼8 g/kg alliin. A pure dehydration process, with no loss of ingredi-
ents, would result in 20–25 mg/g alliin content in the powder. However, garlic powders
contain only 10 g/kg alliin at most, indicating that most of alliin is lost during dehydration.
Crushed raw garlic is high in allicin, containing ∼37 mg/g.[28] Diallyl thiosulfinate (allicin)
 ALLICIN AND FUNCTIONAL ACTIVE COMPONENTS IN GARLIC 247

Figure 1 Structure of allicin; B: Structure of alliin.

was found to be a major constituent of solvent extracted garlic. Diallyl thiosulfinate under-
goes dehydration, leading to the formation of 2 isomeric disulfides by a transformed rear-
rangement. After 24 hours, sulfur dioxide, diallyl mono-, di- and trisulfides were the
major products of this reaction.[29] Allyl and methyl sulfides are main components of com-
mercial garlic oils. Allicin is more or less rapidly degraded into diallyl disulfide,
vinyldithiins, and ajoenes, depending of the conditions: concentration, temperature and
pH.[30] Allicin, when exposed in heated aqueous solution, forms a lipid-soluble oligosul-
fide known as diallyl disulfide.[31] Allyl mercaptan is an odorous compound that is the
main component of garlic breath after eating garlic cloves. Allyl mercaptan is quantita-
tively formed from allicin or diallyl disulfide with cysteine via the intermediate compound
S-allylmercaptocysteine when it comes in contact with whole blood.[32] Allyl mercaptan,
or a further metabolite of it may be the major means of the pharmacological (nontopical,
nonenteral) action of allicin or diallyl disulfide.[32]
Twenty-four botanical traits of Iranian garlic ecotypes were studied for its allicin
content measured by HPLC method.[33] Allicin content ranged from 0.16–13.0 mg/g.
There was no significant correlation between the ecological condition and the allicin
content. Cluster analysis on morphological and phytomedical characters arranged the
ecotypes in six main groups. The ecotype of group A showed the highest botanical and
pharmaceutical potential which could be considered in future breeding programs. Baghalian
et al.[33] pointed that probably the genetic factors could have more influence than ecology.
Commercial allicin and allicin potential (alliin and alliinase activity) are being considered
as indices for evaluation of the medicinal value of garlic preparations.
Lawson and Hughes[34] studied the effects of pH, neutralization after acidification,
time, and temperature on the yield of thiosulfinates release from garlic powder and garlic
cloves. All dipropenyl thiosulfinates including allicin were formed at an optimum pH of
4.5–5.0. Below pH 3.6 no thiosulfinates were formed. Neutralization of the pH (previously
at 3 or below) failed to restore thiosulfinate generation, thus allinase is completely and
irreversibly inhibited by the acidic conditions found in the stomach. Yu and Wu[35] studied
the effects of pH on the formation of flavor compounds from allicin. They found two iso-
meric cyclic compounds 3-vinyl-1,2-dithiin and 2-vinyl-1,3-dithiin reached their highest
levels around pH 6.5, whereas the formation of diallyl trisulphide, diallyl disulphide,
methyl allyl disulphide, and diallyl sulphide was favored around pH 9.0. The effect of
temperature (2–37°C) was found negligible on the rate of thiosulfinates formation. Allicin
is formed from alliin by the action of allinase and gets metabolized rapidly into diallyl
248 RAHMAN

sulfide, diallyl disulfide, diallyl trisulfide, ajoene, S-allylmercaptocysteine, S-allyl cys-

teine, and vinyl dithiines.[15,36,19,37,38]
The maximum rate of formation of allicin from garlic was observed at incubated
temperature of 35°C, retarding effect of acetic acid (5–30%) or rectified spirit (5–30%).
An increased rate of formation was evident with an increase in the pH (4.0–6.0) of the
macerating medium.[39] Similarly the rate of decomposition of allicin formed was found to
be a maximum at incubation temperature of 35°C. The rate decreased with an increase in
the strength of acetic acid, whereas rectified spirit/ethanol (5–30%) showed little effect.
An increased pH (4.0–6.0) resulted in an increased rate of decomposition of allicin.[39]
Raw garlic, when cut and placed on the tongue or lips, elicits painful burning and
prickling sensations. Allicin and diallyl disulfide excite an allyl isothio-cyanate sensitive
subpopulation of sensory neurons and induce vasodilation by activating capsaicin sensi-
tive perivascular sensory nerve endings.[40] Macpherson et al.[41] showed that raw but not
baked garlic activates TRPA1[40] and TRPV1, two temperature-activated ion channels that
belong to the transient receptor potential (TRP) family. These thermo-TRPs are present in
the pain-sensing neurons that innervate the mouth. It was showed that allicin, an unstable
component of fresh garlic, is the chemical responsible for TRP1 and TRPV1 activation
and likely to cause garlic’s pungency.
The loss of allicin in organic solvents during storage at −16 and 6°C was very low
compared to storage at room temperature.[2] At room temperature, it reduced to 10%
within 3 days when stored in ethyl acetate, while in methanol it took around 13 days. This
showed greater stability of allicin in methanol than in ethyl acetate. Iberl et al.[42] reported
that allicin was more stable in solvents capable of hydrogen bonding. Lawson and Gardner[43]
studied the composition (14 sulfur and 2 non-sulfur compounds) of fresh and commercial
tablets, stability of potential active compounds, and availability of allyl thiosulfinates
(mainly allicin) under both simulated gastrointestinal conditions and in vivo. The allyl
thiosulfinates of blended fresh garlic were stable for at least 2 years when stored at −80°C.
The dissolution release of thiosulfinates from the enteric-coated garlic tablets was found
to be >95%. The bioavailability of allyl thiosulfinates from these tablets, measured as
breath allyl methyl sulfide, was found to be complete and equivalent to that of crushed
fresh garlic. S-allylcystein was stable for 12 months at ambient temperature. Stability of
thiosulfinates of crushed garlic at 4°C in the absence of selected condiment revealed no
significant decrease in any of the thiosulfinates at 12 days.
Drying of garlic at 60°C had no effect on alliin since there was only a 4% loss in
yield for allicin, allyl methyl thiosulfinates and dimethyl thiosulfinates. However there
was about 75% loss in yield for each of the 1-propenyl thiosulfinates, indicating that the
drying process had destroyed much of the isoalliin.[34]

FUNCTIONALITY OF ALLICIN AND OTHER ACTIVE COMPONENTS

Antimicrobial Activity
It was reported that allicin showed antibiotic activity.[1,21,44,45] Subramanyan
[46]
et al. studied in vitro the effect of some of the more commonly used spices on intestinal
bacteria in health and disease and reported that garlic was most potent in inhibiting the
growth of some bacteria. Incorporation of garlic in the diet on caecal microflora of rats
showed that garlic could considerably reduce the microflora in synthetic and stock diet fed
animals.[46] A significant decrease in caecal flora of rats was observed in rats fed poor rice
 ALLICIN AND FUNCTIONAL ACTIVE COMPONENTS IN GARLIC 249

diet supplemented with red gram dhal or butter milk along with garlic for 5 days. Nakagawa
et al.[47] reported the death and/or retarded growth in rats fed 5 ml of raw garlic extract per
kg body weight. After feeding raw garlic extract for a period of 4 weeks to albino rats
there was a decrease in total Streptococci, Coliforms, Lactobacilli, aerobes, and anaer-
obes. The effect on aerobes and anaerobes was found equally pronounced. None of the
above changes were observed after feeding boiled garlic extract, instead stimulated the
growth of certain intestinal bacteria, such as Streptococci and Coliforms.[48] When garlic
extract containing 8 μM of allicin was administered intragastrically to albino rats, a maxi-
mum of 0.4 μM in the intestine and 2.4 μM in caecum was detected after a period of 4 and
6 hr, respectively.[49] About 50–60% reduction in microflora was observed in intestine
after 4 hours of administration, but no such change was observed in caecum even after
6 hours. However, a 5-fold decrease in microflora was seen in caecum only at the end of
8 hours. Shashikanth et al.[49] pointed that the gradual decrease in allicin content while
passing through the gut is perhaps due to reducing agents in the gut, natural instability of
allicin, antagonism by food materials and absorption in the intestine. Generally, the aerobes
were more susceptible to allicin concentration in the gut than the anaerobes.
Sharma et al.[50] demonstrated in vivo antibacterial property of Allium sativum water
extracts on gram negative and gram positive flora of the gastro-intestinal tract of chicks
indicating its effectiveness in inhibiting both types of flora. Garlic extract also inhibited
some bacterial flora, which were resistant to some of the antibiotics used. Kumar and
Sharma[51] further indicated the inhibitory effect of garlic on enterotoxigenic Escherichia
coli. The anti-microbial activity of a range of garlic products including dried garlic pow-
der produced by different methods, commercial garlic products, and garlic oil was deter-
mined against a range of selected bacteria (Staphylococcus aureus, Escherichia coli,
Salmonella typhimurium, Bacillus cereus, and a mixed lactic culture consisting of Lacto-
bacillus delbrueckii subsp. Bulgaricus and Streptococcus thermophilus).[52] Generally
fresh garlic produced the greatest inhibition followed by freeze-dried powder. The results
showed that both drying temperature and time had major effects on retaining the active
components responsible for the inhibition of microbial growth. Allicin showed antibacte-
rial effect against Helicobacter pylori.[53] Helicobacter pylori is considered to be one of
the main reasons of gastric and duodenal ulcers as well as gastric cancer. In vitro and
in vivo research proved that Helicobacter pylori, resistant to many antibiotics, was sensi-
tive to garlic extract in relatively low concentrations. Sivam et al.[54] investigated the anti-
microbial activity of aqueous extract of garlic against H. pylori and found that minimum
inhibitory concentration of the extract was 40 μg allicin/ml. Cellini et al.[55] tested 16 clin-
ical isolates of H. pylori and showed the concentration of garlic extract required to inhibit
the bacterial growth was between 2 and 5 mg/ml. The inhibitory concentration of garlic
reported in the above studies is achievable in the stomach by consuming a medium size
clove of garlic. Interestingly, H. Pylori can survive and grow in the acidic environment of
stomach by producing abundant amounts of enzyme urease, which hydrolyzes urea
present in gastric juice. The ammonia, generated from this reaction, produced a local alka-
line microenvironment, thereby protecting the bacterium against the hostile acidic condi-
tions.[56] Juszkiewicz et al.[57] found allicin or garlic extract inhibited the urease attributed
to the reaction of allicin with SH-group. Thiol reagents (L-cysteine, 2-mercaptoethanol,
glutathione, dithiothreithol) strongly protect the enzyme from the loss of enzyme activity,
while urea and boric acid showed weaker protection.
Bakri and Douglas[58] studied the inhibitory effect of garlic extract with allicin on
oral bacteria including 13 gram-positive and 6 gram-negative types of bacteria, and one
250 RAHMAN

type of fungi. The garlic extract 57.1% (w/v) containing 220 μg/ml allicin inhibited the
growth and killed most of the organisms tested. In general, the minimal inhibitory concen-
trations for Gram-negative strains varied from 0.4–6.87 μg/ml which were lower than
those for Gram-positive strains (13.8–55.0 μg/ml) tested. Time-kill curves for Streptococ-
cus mutans and Porphyromonas gingivalis showed that killing of the later started almost
immediately, whereas there was a delay before S. mutans was killed. The garlic extract
also inhibited the trypsin-like and total protease activity of P. gingivalis by 92.7% and
94.88%, respectively.
Garlic extracts showed to be antifungal[59] and antiviral[11] and antiprotozoal[60]
activity. Cu2+ showed a dose dependent fungicidal activity against Saccharomyces cerevi-
siae cells, and its lethal effect was extremely enhanced in the presence of allicin.[61] Allicin
influenced the mode of cell surface localization or the related function of AHP1 as a
defense against phospholipids peroxidation by the external action of Cu2+.
There are several physiological processes in microorganisms which were affected
by allicin, such as lipid bisynthesis[62,63] RNA synthesis,[64] lowering of lipids in mam-
mals,[65,66,67,68,69,70,71] and aggregation of platelets.[72,73] Allicin was shown to be a specific
inhibitor of acetyl-CoA synthetases from plants, yeast, and mammals. The bacterial
acetyl-CoA-forming system, consisting of acetate kinase and phosphotransacetylase was
inhibited. It was found to be specific to the enzymes of the fatty acid synthesis
sequence.[74] Allicin reacts very rapidly with free thiol groups, via thiol-disulphide
exchange, therefore it is thought that its main mechanism of antimicrobial action is
through interaction with thiol-containing enzymes, including cysteine proteases and alco-
hol dehydrogenases.[75,76]

Anticancer Activity
Alliin itself did not show any inhibition of tumor cell growth indicating that the anti-
proliferative effects of garlic was due to breakdown products of alliin.[77] Allicin plays a
major role in the antiproliferative effect of water-soluble garlic preparations and this effect
may be attributed to the ability of allicin to transiently deplete the intracellular
gluthathione (GSH) level. The extent of the decrease in GSH levels correlated well with
the growth inhibitory activity of allicin.[36] The antiproliferative effect of garlic is also
clear. Allyl sulphur compounds are important antitumorigenic agents[78] and diallyl disul-
fide reduced the size and the number of preneoplastic foci in rats liver induced by
AFB1.[79]
The protection of garlic against cancer aroused from several mechanisms including
the blockage of nitrosamines formation and bioactivation.[80] These substances are much
suspected to be carcinogens and influence the cancer risk in humans. Dion et al.[81]
reported that their formations were retarded by S-allylcysteine. Garlic also decreased the
bioactivation of carcinogens. Cytochrome P4502E1 is a hepatic phase I enzyme impli-
cated in the metabolism of nitrosamine, and others carcinogens, and its activity is modu-
lated by organo-sulfur compounds[82] such as diallyl disulfide.[83,84] Ograno-sulfur from
garlic blocked the bioactivation and carcinogenicity of non-nitrosamines such as aflatoxin
B1 (AFB1), a cancer agent for the liver. Phase I enzymes CYP1A1, 1A2, 2B1, and 3A4
involved in carcinogen bioactivation showed a modified activities after diets supplementa-
tion in rats with garlic or several sulfur compound such as diallyl disulfite.[85] The induc-
tion of phase II enzyme detoxication such as glutathione-S-transferase (GST), quinone
reductase (QR), and uridinediphosphoglucuronate glucuronosyltransferase (UGT) by
 ALLICIN AND FUNCTIONAL ACTIVE COMPONENTS IN GARLIC 251

OSC, such as diallyl disulfite[86,87] was demonstrated and similar effects were observed
with garlic consumption.[88,89]
Garlic intake can modify the risk of colon cancer to women because diallyl disulfide
is an effective inhibitor of the growth of neoplastic CMT-13 cells and of N-acetytransferase
activity in human colon adenocarcinoma cell line.[90,37] Furthermore, diallyl disulfide
showed to be an effective inhibitor for the promotion phase of 9,10-dimethyl-1,2-
benzanthracene induced skin tumors in the mouse.[91]
Apoptosis, or programmed cell death, is a genetically controlled process, wherby the
cell actively participates in its own destruction in response to environmental or develop-
mental cues. Apoptosis is morphologically characterized by membrane blebbing, cyto-
plasmic, nuclear and chromatin condensation, and DNA fragmentation.[92] Allicin showed
effects on DNA processing, RNA synthesis,[93] signal transduction and apoptosis.[94] Cer-
tain effects of allicin are mediated through nitric oxide formation.[78] Oommen et al[95]
studied the chemo-preventive action of allicin on the growth of cancer cells of murine and
human origin by cell viability assay. They found that allicin inhibited the proliferation of
cancer cells and induced apoptosis with typical features such as apoptotic bodies, DNA
fragmentation, activation of caspases and poly (ADP-ribose) polymerase cleavage, thus
these effects of allicin account partly for the anticarcinogenic properties of garlic. Park et al.[96]
showed that allicin induced apoptosis of the cells through caspase-independent apoptosis
pathway, which was accompanied by the mitochondrial release of AIF and protein kinase
A (PKA) appeared to play an important role in the caspase-independent apoptosis.
Shalinsky et al.[97] studied the effects of allicin on other terminal prostaglandin bio-
synthetic enzymes, such as isomerase for PGE2 and on cyclooxygenase activity. They
found that allicin selectively inhibited the GSH dependent PGH2 to PGE2 isomerase in the
adenocarcinoma cell line. Macrophages play an important role in host defenses against
tumors by killing them and produce secretory products, which resulted in the protection
against bacterial, virus infection and malignant cell growth. Allicin is an efficient immu-
nomodulator of macrophage secretory and cellular activities; it showed a differential
effect on production of cytokines and cytotoxic molecules.[98] It altered cellular functions
of macrophages to kill tumor cells and produce various molecules, such as NO, H2O2,
TNF-α, IL-1 (interleukin-1) and IL-6 after treated with various doses (1, 10, 100 ng/ml)
for 20 hours.
Allicin and its corresponding sulfite inhibited the proliferation and induced apopto-
sis of several human non-leukaemia malignant cells including breast, bladder, colorectal,
hepatic, prostate cancer, lymphoma, and skin tumor cell lines.[99] Ajoene (which has
greater chemical stability) showed to inhibit proliferation and induced apoptosis of human
leukaemia CD34-negative cells including HL-60, U937, HEL and OCIM-I.[100,15,101,102]
More significantly, ajoene showed to induce 30% apoptosis in myeloblasts from a chronic
myeloid leukaemia patient in blastic crisis.[100,15] Acute myeloid leukaemia, is a heteroge-
neous malignant disease, has a major impact on resistance to chemotherapy and
relapse.[103,104] Ajoene significantly enhanced the inhibitory effect of the two chemothera-
peutic drugs, cytarabine and fludarabine on bcl-2-expression in KG1 cells.[100] The two
key antileukaemia biological actions of ajoene were the inhibition of proliferation and the
induction of apoptosis. Studies showed the anti-proliferation activity of ajoene to be asso-
ciated with a block in the G2/M phase of cell cycle in human myeloid leukaemia cells. The
apoptosis inducing activity of ajoene is via the mitochondria dependent caspase cascade
through a significant reduction of the anti-apoptotic bcl-2 that results in release of cyto-
chrome c and the activation of caspase-3. Since acute myeloid leukaemia (AML) is a
252 RAHMAN

heterogeneous malignant disease in which disease progression at the level of CD34-

positive cells has major impact on resistance to chemotherapy and release and the inability
to undergo apoptosis is a crucial mechanism of multi-drug resistance in AML patients.[99]

Antioxidant Activity
It was reported that soybean oil increased the stability of garlic flavor while cooking
garlic with an oil-water mixture[105] and garlic flavor acted as an inhibitor of soybean oil
oxidation.[106] Kim et al.[107] studied the antioxidant activity of garlic homogenates
blended with distilled water and different amounts of oil. Antioxidant activity of garlic
aroma concentrate in the oil layer was found strong. Diallyl disulfide was found to be most
stable compared to other two sulfur compounds disulfide and diallyl trisulfide when ana-
lyzed by HPLC. It was found that the effectiveness and strength of diallyl disulfide as an
antioxidant could be increased by addition of α-tocopherol and L-ascorbyl palmitate in a
lard system.[107]
In vitro allicin acts by reacting with free thiol containing enzymes, serving as an
efficient antioxidant by trapping of radicals.[108,76] Allicin was found to scavenge hydroxyl
radicals[109,110] and to inhibit superoxide production by phorbol ester-activated human
granulocytes.[77] Allicin showed the modification of SH-dependent activities, an addi-
tional therapeutic property,[109,76,110] and inhibitory effect on NO formation.[78] Ajoene
also showed the inhibitory effect of NO formation.[78] The inflammatory environment in
human atherosclerotic lesions resulted in an expression of the inducible form of nitric
oxide synthase and subsequently in the formation of peroxynitrite. Peroxynitrite is a
potent oxidant, which is formed when the synthesis of large amounts of NO coincides with
superoxide production.[111] Peroxynitrite is able to initiate LDL oxidation and to promote
platelet aggregation[112] and thus aggravates the atherogenic process. Peroxynitrite forma-
tion, however, occurred only if NO is produced in high enough concentrations to compete
endogenous superoxide dismutase for superoxide. In D-galactosamine/lipopolysaccharide
induced hepatitis rats, a significant increase of lipid peroxidation and decreased liver anti-
oxidant enzyme levels were observed. Pretreatment with allicin prevented these alter-
ations, thus provided hepatoprotective effect.[113] Allicin showed antigenotoxic effect
against methyl methanesulphonate induced genotoxic damage.[114]

Reducing Cardiovascular Diseases

Cardiovascular diseases include a great number of factors such as high cholesterol,
hypertension and increased platelet aggregation. The role of garlic in the reduction of car-
diovascular diseases was historically proved but contradictory clinical studies emerged
from different methodologies.[30] The hypotensive effect is one of the earliest established
properties of garlic preparations and was later confirmed in animals[115] and in
humans.[116] The health benefit observed varies with the garlic products tested, i.e., garlic
powder, aged garlic extract, garlic oil, and garlic oil macerate,[6] with the state of cooked-,
raw-, fried-, or boiled-garlic[117,118] and with the percentage of active components.[119] The
contradictory results may be due to several factors and the lack of knowledge about the
substances present is certainly one of them.[30] Garlic reduced blood pressure,[67,120] anti-
oxidant,[121] inhibited platelet aggregation,[27,70] and reduced blood glucose.[67]
Allicin altered the lipid profile in hyperlipidemic rabbits.[122] Synthetic preparation
of allicin was found to lower blood pressure, insulin, and triglycerides levels in fructose-fed
 ALLICIN AND FUNCTIONAL ACTIVE COMPONENTS IN GARLIC 253

rats.[123] Similar beneficial effect of allicin and enalapril (hypertensive drug) on blood
pressure, insulin, and triglycerides were observed in fructose-induced hyperinsulinemic,
hyperlipidemic and hypertensive rats, thus it reinforces the trend toward combining the
nonpharmacologic approach with drug therapy.[124] It also reduced the gain in weight of
the groups fed fructose with allicin.[125]
Atherosclerosis is one of the major risk factor in the development of hypertension
and cardiovascular diseases. For centuries, garlic has been used for treating high blood
pressure in China and Japan. Furthermore, garlic has been found to act as an antihyperten-
sive agent[126,127] and has been officially recognized for the treatment of hypertension by
the Japanese Food and Drug Administration.[128] In hypercholesterolemic rabbits garlic
elicited a significant reduction of the hypercholesterolemia in a way comparable to gemfi-
brozil while serum triglycerides values remain unchanged after garlic treatment.[129]
Ali et al.[4] studied the effect of garlic powder (0.6% allicin) on the serum cholesterol, triglyc-
eride, glucose, protein, and systolic blood pressure in rats fed with a high cholesterol diet.
They found significant reduction in serum cholesterol, triglycerides, and blood pressure
level, thus providing that garlic has beneficial functions. Effect on two risk factors for ath-
erosclerosis: hyperlipidemia and hypertension. However, no changes were observed in the
serum glucose and protein in all of the rats. Allicin showed significant vasodilator activity
in the pulmonary vascular bed of rat when tone is increased experimentally. However,
diallyl disulfide and allyl mercaptan, metabolites of allicin, did not possess this vasodila-
tor action.[31] Although the mechanism by which allicin induces vasosidilatation is uncer-
tain, the results of the investigation of Kaye et al.[31] suggest that this garlic derivative may
be useful in the treatment of pulmonary hypertensive disorders, including primary pulmo-
nary hypertension and chronic obstructive pulmonary disease. Allicin also showed vasodi-
lator activity in the pulmonary vascular bed of cat and rat.[130] When baseline tone in the
pulmonary vascular bed of cat was raised, intralobar injections of allicin produced dose-
related decrease in pulmonary arterial pressure without changing left arterial pressure.
Allicin also decreased systemic arterial pressure in a dose-related manner.[130] The pulmo-
nary vasodilator responses to allicin were independent of the synthesis of endothelial
derived relaxing factor or the activation of soluble guanylate cyclase. Other allicin analogs
should be developed for clinical use because of allicin’s vasodilator efficacy and apparent
lack of toxicity.[31] A modest dose (14 mg of allicin) was shown to cause decrease in dias-
tolic blood pressure in severely hypertensive patients.[131]
Inflammatory diseases such as atherosclerosis lead to coronary thrombosis. The
platelet aggregation contributes to minimize the atherosclerosis, and it was reduced by
allicin and two others thiosulphinates from onion.[132] The antiplatelet activity in onion
was significantly positively correlated with high sulfur level.[133] Garlic powder also
inhibited the platelet aggregation.[134] Lawson et al.[27] reported the variation of the anti-
platelet activity of different garlic preparation, cloves or commercial products. These vari-
ations are due to the different nature of organo-sulfur compound present. Extracts of garlic
was found to inhibit human platelet aggregation in vitro.[135] The inhibition of human
platelet aggregation did not involve an effect on cyclooxygenase thromboxane synthase
activity, or on adenosine 3′, 5′-cyclic monophosphate levels.[73]
Miron et al.[136] synthesized allylmercaptocaptopril (CPSSA) by reacting captopril
(antihypertensive drug, antiotension converting enzyme inhibitor) with pure allicin and
studied their effects on fructose induced hypertensive groups of rats. They found that
CPSSA decreased blood pressure and reduced triglycerides, whereas it found no effect on
the insulin serum level. This new stable compound combines the beneficial properties of
254 RAHMAN

captopril and allicin and is a potential candidate for antihypertensive drug therapy. In rats,
treatment with low dose of CPSSA (5 mg/kg day) lowered SBP but did not improve any
further measured parameter, while treatment with a higher dose (50 mg/kg day) signifi-
cantly decreased blood pressure, triglycerides, and homocysteine concentrations.[137]

Improving Immune Function

Garlic decreases certain diseases caused by immune dysfunction. Thus, aged garlic
extract presents an immunomodulation effect.[138] The immunomodulatory effect of garlic
or garlic constituents shows a modulation of cytokine production as mediator of inflam-
mation. The nuclear factor-KB (NF-KB) is a central transcription factor and has a central
role in the expression of genes that control immune response. NF-KB is strongly involved
in the activation and regulation of key molecules associated with inflammatory diseases
and cancer.[139] It increases the expression of the genes of some cytokines. The inhibition
of NF-KB by garlic products was indirectly controlled by a modulation of pro- and anti-
inflammatory cytokines.[140] Epithelial cells have an important role in intestinal inflamma-
tion and allicin showed anti-inflammatory properties.[141] Allicin inhibited spontaneous
and TNF-α induced secretion of pro-inflammatory cytokines and chemokines from intestinal
epithelial cells.[141] Josling[142] found that an allicin containing supplement can prevent
attack by common cold virus. One hundred forty six volunteers were randomized to
receive a placebo or an allicin-containing garlic supplement, one capsule daily, over a
12-week period. The active treatment group had significantly fewer colds than the placebo
group. The placebo group, in contrast, recorded significantly more days challenged virally
and a significantly longer duration of symptoms.

Effect on Protein and Fat Profile

Augusti and Mathew[66] showed decreased serum protein levels in rats administered
raw garlic extract. Raw garlic extract showed decreased total serum proteins as well as
serum globulin when fed albino rats for 4 weeks, whereas boiled garlic extracts did not
show any effects.[48] The long term feeding (4 weeks) of raw and boiled garlic extract to
albino rats resulted weight loss.[48] Extracts of garlic were also reported to possess
hypoglycemic[121,143] and hypocholesteremic properties.[66] Allicin also reduced serum
cholesterol and triglyceride levels, as well as atherosclerotic plaque formation, prevented
platelet aggregation and decreased blood pressure.[144,62,24,145]

BIOAVAILABILITY OF ALLICIN
Figure 2 shows different pathways of active components in the body. Before one can
evaluate the effectiveness of allicin in the body, it must be determined whether or not it
can actually reach the target organs.[58] If allicin or an allicin containing substance is
ingested, it would be exposed to the acidic conditions of the stomach and then to the neu-
tral conditions of the intestines. For these reasons, Freeman and Kodera[2] studied the rela-
tive stability of allicin in blood, different solvents [ethyl acetate, methanol, water (pH 1.2
and 7.5)], simulated gastric fluid (SGF, pH 1.2), and simulated intestinal fluid (SIF, pH
7.5). At 37°C, allicin decomposed rapidly in methanol and ethyl acetate, however, it was
more stable in protic polar methanol than in aprotic polar ethyl acetate. Approximately
90% of allicin remained after incubation at 37°C for 5 hours in water at pH 1.2 and 7.5.
 ALLICIN AND FUNCTIONAL ACTIVE COMPONENTS IN GARLIC 255

Formation

Transformation

Stomach

Stability, Functionality, Health

Intestine

Blood

Organ

Breath Exhaust Urine

Stool

Figure 2 Cycle of active components in body.

After 1 day at pH 1.2, about 80% of allicin remained, and at pH 7.5, about 62% of allicin
remained. Interestingly, allicin did not appear to generate its normal transformation prod-
ucts at these pH values since an increase in the concentration of diallyl disulfide, ajoene,
and dithiin was not observed. Therefore, gastric or intestinal pH may not be a significant
factor affecting allicin availability or decomposition in the body during the digestive
period. There was likely to inactivation of allinase, the enzyme that catalyzes the conver-
sion of alliin to allicin at ≤ pH 3.[34]
Food substances are normally present in the gastrointestinal tract, thus interaction of
allicin with cow’s milk was also examined by Freeman and Kodera.[2] After exposure of
milk for 1 hour, almost all allicin was recovered. Only traces of allicin could be detected
after it was incubated in blood for 5 minutes. Allicin was more reactive to the blood cell
fraction than to the plasma fraction. No allicin was detected after 3 minutes when it was
incubated in blood cell fraction, while in the plasma fraction, the concentration of allicin
decreased gradually and the half-life of allicin was estimated to be about 50 minutes. A
rapid change in color of red blood cells to a dark color was observed after addition of alli-
cin, which may be due to the rapid oxidization of iron in hemoglobin. Concurrent with the
disappearance of allicin, the presence of diallyl disulfide was observed in the mixture of
allicin and blood. Diallyl disulfide showed stability in blood. The concentration of diallyl
disulfide remained unchanged after 1 hour.
Similar results were also observed in case of liver cell.[146] After incubation for
3 minutes in liver homogenate, a decrease of 90% initial allicin was observed and
the decrease of allicin was 99% after 6 minutes. On the other hand, it was observed that
the metabolism of diallyl disulfide in mice reached a maximal concentration in the liver
after 90 minutes of jp injection.[147] Although allicin disappeared rapidly in the body after
256 RAHMAN

absorption, diallyl disulfide may be absorbed and delivered to organs.[146,147] Egen-

Schwind et al.[146] investigated pharmacokinetics of vinyldithiins (transformation products
of allicin) after oral administration of 27 mg 1,3-vinyldithiin and 9 mg of 1,2-vinyldithiin
to rats. In serum, kidney, and fat tissue, both vinyldithiins were detected over a period of
24 hours, whereas in liver only 1,3-vinyldithiin was found. 1,3-vinyldithiin seems to be
less lipophilic and was rapidly eliminated from serum, kidney, and fat tissue, whereas
1,2-vinyldithiin is more lipophilic and showed a tendency to accumulate in fat tissue. Allicin,
the precursor of vinyldithiins, is metabolized more rapidly in liver homogenate than the
vinyldithiins. Allicin is assumed to be the active component of garlic in vivo, but not in
vitro. Allicin cannot be detected in the blood or urine after the ingestion of raw garlic or
pure allicin within 1 to 24 hours after ingestion of 25 g raw garlic (∼90 mg allicin).[27]
It was reported that allicin can be produced by human liver microsomes from diallyl
disulfide. These suggested that despite its rapid disappearance from the bloodstream, alli-
cin can be reformed in the process of interconversion of its metabolites and as a result, act
intracellularly.[148] Agarwal[65] suggested that metabolites of allicin, rather than the agent
itself, are responsible for this wide range of beneficial health effects. Several such metab-
olites are S-allylmercaptocysteine, diallyl sulfide, diallyl disulfide, diallyl trisulfide,
ajoene, and S-allylcysteine. The pharmacokinetic studies of S-allyl cysteine demonstrated
rapid absorption and almost 100% bioavailability after oral administration. In addition,
since both safety and effectiveness of S-allyl cysteine have been reported, this compound
appeared to play an important role in garlic’s medicinal effects.[149,150]
Freeman and Kodera[2] also studied the allicin content and allicin-producing poten-
tial of commercial garlic preparations. No allicin was observed in all commercial prod-
ucts. Although no product on the market contains a detectable amount of allicin (< 1 ppm)
some garlic powder products claim to be able to generate certain amount of allicin, so-
called “allicin potential” or “allicin yield.” Variable allicin potentials from 0.64–4.64 g/kg
were observed in different brands of products, as well as among different lots of the same
brand. After 1 hour at 37°C under SIF conditions, about 62% (2.86 g/kg) of the amount of
allicin produced with water was observed, and after 1 hour under SGF condition, only 4%
(0.19 g/kg) could be found. This low level of allicin production under SGF condition may
be due to hydrolysis of allinase by acid and enzyme pepsin. Under simulated digestive
conditions (sequential combination of SGF and SIF), only about 1% of allicin was
observed. The small amount of allicin observed is not due to its decomposition during the
incubation period because it was shown to be stable at gastric and intestinal pH for 2 to 3
hours. At pH 6.8 commercial products released very fast highly soluble compounds,
amino acids, and dipeptides.[30] Within less than 5 minutes nearly 100% of these com-
pounds were released and allicin was formed. Alliin was very fast released from the pow-
der and immediately metabolized to allicin (100%) within the pH range of 3.5–8.4. At pH 2,
alliin was completely released within a minutes without further degradation to allicin.
Higher pH values seem to stabilize the allicin, whereas lower pH values accelerated its
degradation. However, sulfides and dithiines could not be detected in the release media
within 30 minutes.[30]
Arnault et al.[30] analyzed alliin, allicin, and storage stability of 11 European prod-
ucts and found the majority of the products present a very different composition from
what was claimed by the companies. Only one product possessed the legal status of a
drug. For that product, values were found as claimed on the package. It was known that
alliin and allicin content decreased in correlation to their storage time. This can be
explained by the residual activity of the allinase. Their results clearly showed the instability
 ALLICIN AND FUNCTIONAL ACTIVE COMPONENTS IN GARLIC 257

of products when stored under ambient conditions for 18 months. The best products
remained activity of 70–90%, whereas most of the products showed below 50% value.
The BET monolayer value of freeze-dried garlic, which is considered as most stability of
dried products during storage, was found 5.7 g/100 g sample at 20°C.[151] However,
Arnault et al.[30] recommended residual water of less than 3 g/100 g sample (i.e., 3%), and
a complete water vapor tight packaging material is needed for keeping their functionality.
In addition, high packing of the tablet and organic film coating could also improve the sta-
bility up to 24 months.
The certitude that garlic provides beneficial effects on health lead the industry to
market some garlic market products for human consumption in the last decades. There are
2 major types of market garlic products on the European pharmaceutical and food supple-
ment market and a third one on the American market: (a) the oil macerates of fresh garlic,
formulated commonly in soft gelatin capsules; (b) the dry powder products of fresh garlic
formulated either as sugar or film coated tablets; and (c) dry powder products of aged garlic
formulated either as sugar or film coated tablets.[145] It is the task of the pharmaceutical
science to formulate each active principle individually in such a way that the active princi-
ple is fully available under the physiological condition of the application. The appearances
and characteristics of medicinal products are significantly influenced and controlled by
the formulation technology (galenic) and the analytical technology. Both determine the
ability to manufacture quality/stability, efficacy, and consumer acceptance of the final
medicinal product.
Although not all of the active ingredients are known, ample research suggested that
several biological components likely contribute to the observed beneficial effects of
garlic.[6] Other active organosulfur compounds found in garlic derived from allicin are
diallyl disulfide, methyl allyl trisulfide, and ajoene. Allylic and allenic thiosulfinates are
of biological interest due to their similarity to allicin. Braverman et al.[152] developed a
convenient preparation method of mixed allyl allenic and bis-allylic thiosulfinates.
Being a chemically reactive compound and hence rather unstable, allicin rapidly
transforms into a number of derivatives found in aged garlic and various crushed garlic
preparations. For garlic extract, whole or sliced garlic cloves are soaked in an extracting
solution (e.g., purified water and diluted alcohol) for varying amount of time. After sepa-
ration of the solution the extract is generally concentrated and used.[6] Powdered forms of
the extract are also available. The extract, especially aged, contains mainly the water solu-
ble constituents in garlic and a small amount of oil-soluble compounds.[153] The extract is
characterized by water soluble sulfur containing compounds, including S-allyl cysteine
(SAC) and S-allyl mercaptocysteine.[154] S-allyl cysteine can be used for standardization
because it is bioavailable and can be detected in the plasma, liver and kidney after oral
intake. The bioavailability of SAC was 103% in mice, 98.2% in rats, and 87.2% in
dogs.[155] S-acetyl SAC was identified as a metabolite of SAC in the urine of dogs and
humans. Other metabolites of garlic constituents, such as N-acetyl-S-(2-carboxypropyl)-
cysteine, N-acetyl-cystein and hexahydrohippuric acid, were detected in human urine after
ingestion of garlic.[156] This suggested that SAC could be transformed by N-acetyltransferase.
SAC and its metabolite(s) are possible compliance markers for clinical studies involving
garlic.[157]
Allyl mercaptan and diallyl disulfide were the first compounds identified as compo-
nents that produce the strong odor detectable after ingestion of garlic.[158,159] Allicin, per-
fused into isolated rat livers, showed a remarkable first-pass effect and was metabolized as
diallyl disulfide and allyl mercaptan, whereas ajoenes and vinyl-dithines were recovered
258 RAHMAN

in the effluent.[146] The inhibition ability of platelet aggregation on the basis of ajoene and
dithiin content may be inadequate because other compounds may act synergistically or
independently to bring the effect.[6] For example, aged garlic, which contains neither
ajoene nor dithiin, significantly reduced platelet aggregation and adhesion in two double-
blind, placebo-controlled clinical studies.[160,161] As a result, Amagase et al.[6] pointed that
the concentration of various compounds and their effects in vitro may not determine effec-
tiveness. Preclinical or preferably clinical studies are required to confirm or refute the
effectiveness of a product in question, whatever its chemical composition.
Aged garlic extract is aged for up to 20 months. During the aging process, the odorous,
harsh, and irritating compounds of garlic are converted naturally into stable and safe sulfur
compounds. Further the safety of aged garlic has been confirmed by various toxicological
studies.[162,47,163–166]
Allicin rapidly disappears from the circulation after intravenous injection suggesting
that it is transformed into secondary products.[2,167] A variety of biological effects of alli-
cin are attributed both to its SH-modifying and its antioxidant activity,[75,25,110,109] which
also found in model systems.[168,76] Allicin can easily permeate cell membranes of phos-
pholipids bilayers, carry out its activity intracellularly and interacted with SH groups.[108]
Fast diffusion and permeation of allicin across human red blood cell membranes was also
demonstrated. Allicin did not induce leakage, fusion or aggregation of membrane. The
high permeability of allicin through membranes may greatly enhance the intracellular
interaction with thiols.[108] It is important to find which by-product of allicin is the active
species that modulates extra- and intra-cellularly processes.
It was found S-allylmercaptocysteine (CSSA) as the product of the reaction of
cysteine with allicin.[44] It is one of the active ingredients of aged garlic extract. The
antiproliferative activity of CSSA on different cell lines was demonstrated, whereas S-
allylcysteine showed no such effect.[169–170,19,101] CSSA also revealed antioxidant activity[154]
and decreasing ocular pressure activities.[171] Allicin elevated intracellular Ca2+ concentra-
tion in rabbit nonpigmented ciliary epithelial cells by allicin.[171] The reduced glutathione
most abundant non-protein thiol in mammalian systems has potential to interact with alli-
cin. Rabinkov et al.[172] studied the formation of S-allylmercaptoglutathione (GSSA) upon
interaction of allicin with glutathione. The potential of GSSA to serve as vehicles for the
prolonged action of allicin was demonstrated by its SH-modifying properties and high
antioxidant activity. It showed reduction of OH radical reactions, and lowered the produc-
tion of lipid peroxides. Thus it has a role in the biological activity of allicin and its deriva-
tives. Though individual compounds, such as S-allyl cysteine showed activity, however
Koch[173] emphasized that the activity of various sulfur compounds could not alone be
responsible for the benefits of garlic and fixation on a single group of components can
lead to mistakes and wrong conclusions. Overall, the active principles in garlic was not
fully characterized and 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.[6]

SAFETY AND TOXICITY

The effectiveness of garlic may be prevention rather than therapy, thus it may need
long-term supplementation.[6] Long-term use of supplements raises issues about toxicity.
Although garlic has been used safely in cooking as a popular condiment or flavoring and
used traditionally for medicinal purposes, it is commonly known that excessive consumption
 ALLICIN AND FUNCTIONAL ACTIVE COMPONENTS IN GARLIC 259

of garlic can cause problems. Recently Amagase et al.[6] reviewed the safety of garlic
preparation. Garlic produces odor on breath and skin[174] and occasional allergic reac-
tions.[175] Other adverse effects associated with garlic are: stomach disorders and diar-
rhea,[22,176,47] decrease of serum protein and calcium,[177,48] anemia,[178–179,35] bronchial
asthma[180–181] contact dermatitis,[182–187] inhibition of supermatogenesis[188–189] and dam-
age of intestinal lining and the stomach.[149] The following results were reported by
Imada:[190] (i) allicin is one of the major irritants in raw garlic; (ii) oil soluble sulfur com-
pounds are more toxic than water soluble compounds; and (iii) when garlic is extracted in
water for a certain period, its toxicity is greatly reduced. A number of toxicological and
clinical studies of aged garlic showed no adverse effects. The safety of aged garlic was
established in the following studies: acute and substance toxicity tests,[163,164] chronic
toxicity test,[165] mutagenicity tests,[166] general toxicity tests,[162,47] teratogenicity tests,
toxicity test conducted by the FDA, and clinical studies conducted on > 1000 subjects.[191–193]

CONCLUSION
In 1892, the importance of diallyl disulfide and diallyl trisulfide in the flavor of gar-
lic distillates was established. Allicin (diallyl-thiosulfinate), the most biologically active
compound of garlic was discovered in 1944, and it is noted for its potent antimicrobial
activity. Traditionally, many cultures used garlic for its different biological and medicinal
effects. Based on this belief, trails of whole and garlic extracts started and continued in
human and animal models. Recently attempts were being made to identify the functional
components of garlic and to explore their mechanisms of action in human and animal
models. In addition, other derived compounds from active garlic components are being
developed to be used, which could provide more safety and effectiveness. The dose levels
of effective functions and long-term toxicological safety need to be explored in more
detail.

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