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School of Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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concentrations or serum lipid profiles were observed.
We conclude that AGE, when taken as a dietary supplement by
normolipidemic subjects, may be beneficial in protecting against
cardiovascular disease as a result of inhibiting platelet
aggregation.
KEY WORDS: • platelet aggregation • humans • garlic • ADP • eicosanoids
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). For example,
garlic has been shown to be antitumorigenic (Kyo et al. 1998
, Milner 1996
) and to inhibit a variety of
chemically induced cancers, including those of the breast
(Schaffer et al. 1997
) and skin (Perchellet et al. 1990
). Garlic and some of its constituents have also been
shown to be protective against acetaminophen (Wang et al. 1996
) and bromobenzene toxicities (Wang et al. 1999
).
By far the most widely studied and reported health-promoting effect
of garlic is cardioprotection. Cardiovascular disease is
multifactorial, and garlic appears to exert its beneficial effects at
several different sites in the pathogenesis of the disease. Several
reports have claimed that garlic lowers plasma cholesterol
concentrations, particularly those of LDL (Neil et al. 1996
, Steiner et al. 1996
). More recently, an
aged garlic extract was shown to inhibit directly the formation of
atherosclerotic plaques in de-endothelialized carotid arteries in
rabbits fed a diet supplemented with 1% cholesterol (Efendy et al. 1997
). The oxidative modification of LDL is now recognized
as an important process in the development of atherosclerosis, and
garlic has been shown to inhibit Cu2+-induced
oxidation of LDL in vitro (Ide et al. 1997
) and to
protect cultured vascular endothelial cells from injury induced by
oxidized LDL (Ide and Lau 1997
). In addition,
Munday et al. (1999)
reported that ingestion of an aged
garlic extract
(AGE),3
but not raw garlic, inhibits the oxidation of subsequently isolated
LDL. Finally, garlic has also been shown to have antithrombotic effects
in that it inhibits platelet aggregation in experimental animals
(DeBoer and Folts 1989
) and humans (Bordia et al. 1996
, Lawson et al. 1992
, Legnani et al. 1993
, Steiner and Lin 1998
) at high risk of
cardiovascular disease. Indeed, the only study we are aware of that has
focused on healthy subjects is that of Legnani et al. (1993)
who showed that acute (6 h) and chronic (14 d)
administration of dried garlic powder (Kwai, Liehtwer Pharma GmbH,
Berlin, Germany) inhibited ADP- and collagen-induced platelet
aggregation. In this paper, we report the effects of an AGE (Kyolic)
taken by healthy subjects as a dietary supplement for 13 wk on
ADP-induced platelet aggregation and on the plasma concentrations
of lipids and eicosanoids. In addition, the results of liver function
tests before and after dietary supplementation with AGE are reported.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Aged garlic extract (AGE, Kyolic), kindly provided by Wakunaga of America (Mission Viejo, CA), is formulated by soaking sliced raw garlic (Allium sativum) in 15–20% aqueous ethanol for up to 20 mo at room temperature. The extract is then filtered and concentrated under reduced pressure at low temperature. The content of water-soluble compounds is relatively high, whereas that of oil-soluble compounds is low. The AGE used in this trial contained 305 g/L extracted solids; S-allyl cysteine, the most abundant water-soluble organosulfur compound in AGE, was present at 1.47 g/L.
Subjects.
Apparently healthy subjects (n = 23; 12 men, 11 women, age range 22–45 y) who were not taking medication for any known disease completed the study which had the prior approval of the Ethics Committee of Liverpool John Moores University. Subjects consumed 5 mL of AGE (taken in a small volume of fruit juice) daily for 13 wk between 0700 and 0900 h; otherwise, subjects followed their usual diet and lifestyle (including alcohol intake). Three subjects were smokers. All subjects refrained from taking aspirin or other drugs known to affect hemostasis and/or platelet aggregation for 2 wk before and during the study. Blood samples (34 mL) were taken after an overnight (12-h) fast immediately before ingestion of AGE and under similar conditions after 13 wk of ingestion of AGE (i.e., 24 h after the last dose). The major portion of the sample (27 mL) was added to 38 g/L trisodium citrate in the ratio 9:1 (v/v, blood/anticoagulant) for platelet aggregation studies, and 4 mL was allowed to clot at room temperature for preparation of serum (1500 x g for 20 min) for lipid and liver function assays. The remaining 3 mL of the blood sample was added to EDTA/indomethacin (20 g/L EDTA, 9 g/L NaCl, pH 7.4, containing 2 mmol/L indomethacin) as anticoagulant (9:1, v/v, blood/anticoagulant) for preparation of plasma (1500 x g for 20 min) for eicosanoid assays. Serum and plasma samples for biochemical assays were stored at -70°C for up to 3 mo before analysis.
Platelet aggregation.
Platelet aggregation was determined within 2 h of blood being
drawn. Platelet-rich plasma (PRP) was prepared by centrifugation of
blood at 150 x g for 8 min, whereas
platelet-poor plasma (PPP) was prepared by centrifuging PRP at 1500
x g for a further 20 min. Platelets in PRP were
counted using a Neubauer hemocytometer (Merck Eurolab,
Lutterworth, UK) and, if necessary, the cell count was adjusted to 2.5
± 0.5 x 105 cells/mL by dilution with PPP.
Aggregation was performed in a PAP-4 Platelet Aggregation Profiler
(Bio/Data, Horsham, PA), which was first calibrated using PRP (0%
aggregation) and PPP (100% aggregation). Aggregation was carried out
at 37°C in 0.2 mL of PRP in microvolume tubes and was initiated by
adding ADP (stock 200 µmol/L) to final concentrations
of up to 10 µmol/L. The aggregation curves were
recorded and analyzed using the associated Bio/Data software for total
percentage aggregation and the maximal initial rate of aggregation
(i.e., % aggregation/min). At low concentrations of ADP, aggregation
is biphasic and its rate was derived from the primary wave of
aggregation. To calculate KM and
Rmax values for aggregation from plots of
rate of aggregation (R) vs. ADP concentration
(A), the three classical transformations used for enzyme
kinetic data were applied, namely, Lineweaver-Burk
(1/R vs. 1/A), Eadie-Hofstee
(R vs. R/A) and
Hanes-Woolf (A/R vs.
A) plots (Garrett and Grisham 1995
).
KM and Rmax
values were obtained from regression analysis of each plot.
Biochemical analyses.
Plasma 6-keto-prostaglandin F1
(6-keto-PGF1) and thromboxane B2
(TXB2) were quantified using Amprep C2 columns (100 mg) and
enzymeimmunoassay kits supplied by Amersham International (Amersham,
Bucks., UK). To extract the eicosanoids from plasma, columns were
conditioned by rinsing with 2 mL of methanol followed by 2 mL of
distilled water. Plasma (1 mL) was acidified to pH 3 with 1 mol/L HCl
and applied to the column. The column was washed with 5 mL of each of
distilled water, 10% (v/v) ethanol and petroleum ether before the
eicosanoids were eluted with 5 mL of methyl formate. The methyl formate
eluate was evaporated to dryness under N2 and the residue
redissolved in 250 µL of assay buffer (0.1 mol/L
phosphate buffer, pH 7.5, containing 9 g/L saline, 1 g/L bovine serum
albumin and preservative). Aliquots (50 µL) of the
redissolved extract were assayed for 6-keto-PGF1 and
TXB2 by a horse radish peroxidase-linked
enzymeimmunoassay method according to the manufacturer’s instructions.
Analysis of serum was carried out using a fully automated Monarch 2000
Chemistry System (Instrumentation Laboratory, Warrington, UK). All test
kits and quality control sera were purchased from Boehringer Mannheim
(Lewes, East Sussex, UK). Total cholesterol and triglyceride
concentrations were determined by the CHOD-PAP and GPO-PAP
methods, respectively. HDL was measured as the cholesterol remaining in
the supernatant after precipitation of apolipoprotein B–containing
lipoproteins with heparin/manganese chloride (HDL precipitant,
Boehringer Mannheim). LDL cholesterol was calculated using the
Freidewald equation (Friedewald et al. 1972
). Serum
alanine aminotransferase (ALT) and aspartate aminotransferase were
assayed at 37°C by NAD+-linked reactions. Alkaline
phosphatase and 
-glutamyltransferase were measured at 37°C by
kinetic colorimetric methods utilizing the production of
p-nitrophenol and 5-amino-2-nitrobenzonate,
respectively.
Statistical analysis.
The significance of differences in various parameters before and after AGE supplementation was assessed by Student’s paired t test using the Minitab (State College, PA) statistical package.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). This was most dramatic at low concentrations of ADP (P
< 0.05; 0.5, 1 and 2 µmol/L) when the extent of
aggregation was submaximal. At ADP concentrations 
4
µmol/L, total percentage aggregation was maximal at
70–80% and was not significantly affected by ingestion of AGE.
|
). This was
significant at all concentrations of ADP up to 10 µmol/L.
All three transformations of these data showed that ingestion of AGE
had little effect on the Rmax for
ADP-induced aggregation, whereas the
KM was approximately doubled (P
< 0.007 for the Eadie-Hofstee and Hanes-Woolf
transformations, Table 1
).
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). Similarly, little change was seen with serum enzymes, although serum
ALT was significantly decreased by nearly 20% after ingestion of AGE
(Table 2)
. Plasma concentrations of TXB2 and
6-keto-PGF1 tended to be decreased (32 and
18%, respectively) after ingestion of AGE; however, these decreases
were not significant (Table 2)
.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). In this study, we used a liquid aged
garlic extract (AGE, Kyolic) that contains relatively high
concentrations of water-soluble compounds and low concentrations of
oil-soluble compounds, and is standardized to
S-allylcysteine, its major organosulfur constituent. In
contrast, the major organosulfur compound in the garlic powder (Kwai)
used by Legnani et al. (1993)
was allicin.
Supplementation with AGE had no significant effects on serum total, LDL
or HDL cholesterol and triglyceride concentrations (Table 2)
. This is
in contrast to some previously reported studies (Agarwal 1996
, Lau et al. 1987
, Steiner et al. 1996
, Warshafsky et al. 1993
) and could be due
to the fact that the subjects who took part in our study were
essentially normolipidemic. Using the European Atherosclerosis Society
guidelines, 11 of 23 of our subjects had serum cholesterol
concentrations < 5.2 mmol/L (200 mg/dL), whereas the remaining 12
had concentrations of 5.2–7.8 mmol/L; none exceeded 7.8 mmol/L (300
mg/dL). Lau et al. (1987)
also did not observe a
decrease in serum cholesterol concentrations when the subjects under
investigation were normolipidemic. It has also been reported that a
hypocholesterolemic effect occurs only after long-term (6 mo)
dietary administration of AGE (Lau et al. 1987
). Our
study lasted 3 mo and, indeed, it has been reported that an initial
rise in serum cholesterol is seen in the first 2 mo of AGE
administration with concentrations decreasing by mo 4 (Lau et al. 1987
).
Dietary supplementation with AGE had little effect on liver function as
judged by the serum activity of four enzymes (Table 2)
. However, it is
noteworthy that AGE caused a significant decrease in the serum activity
of ALT. This cytosolic enzyme is released into blood from damaged
hepatocytes. Thus, this observation suggests that AGE is
hepatoprotective and is in agreement with both in vitro (Wang et al. 1999
) and in vivo (Nakagawa et al. 1988
)
studies in animals that have demonstrated that AGE protects against
known hepatotoxins such as carbon tetrachloride and bromobenzene.
Possibly the most important result of our clinical trial was that after
3 mo of dietary supplementation, AGE inhibited both the total
percentage and initial rate of ADP-induced platelet aggregation
(Fig. 1)
. Steiner and Lin (1998
) conducted a similar
study in which 7.2 g of dried AGE (equivalent to 
25 mL of
liquid AGE) was given as a daily supplement to hypercholestolemic men
for 10 mo. In that study, inhibition of platelet aggregation induced by
epinephrine and collagen was seen, but not of aggregation induced by
ADP; inhibition of platelet adhesion to fibrinogen was also seen.
Steiner and Lin (1998)
reported the median effective
concentration (EC50) of ADP for platelet
aggregation to be 1.5 µmol/L, which is similar to the
KM values reported in Table 1
.
Although the EC50 for ADP was unaffected by the
supplementation regimen used by Steiner and Lin (1998)
,
the KM for ADP was approximately
doubled by our supplementation regimen (Table 1)
, indicating a decrease
in the affinity of the platelet ADP receptor for its ligand.
PGI2, the major arachidonic acid metabolite
formed by the vascular endothelial cells, is a potent vasodilator and
inhibitor of platelet aggregation. In contrast, the major arachidonic
acid metabolite formed by platelets is TXA2,
which is a potent vasoconstrictor and stimulator of aggregation. It is
the balance between these eicosanoids that is important in regulating
hemostasis and platelet aggregation. These eicosanoids are extremely
short-lived in plasma and are invariably measured as their stable
metabolites, 6-keto-PGF1 and
TXB2. Supplementation with AGE produced apparent
decreases in plasma 6-keto-PGF1 and
TXB2 concentrations of 18 and 32% respectively
(Table 2)
. However, these decreases were not significant and, perhaps
more importantly, AGE had little or no effect on the balance between
these eicosanoids. This implies that dietary supplementation with AGE
does not affect the cycloxygenase pathway in vivo. Serum
TXB2 was also unaffected 6 h after
administration of 900 mg of dried garlic powder (Kwai), whereas ADP-
and collagen-induced platelet aggregation was inhibited
(Legnani et al. 1993
). However, it must be remembered
that some garlic preparations have been reported to modulate the
cycloxygenase pathway in vitro (Ali and Mohammed 1986
,
Srivastava 1984
)
The production of nitric oxide (NO) by endothelial cells is another
important regulator of platelet activity (Moncada and Higgs 1995
). However, it is not known whether AGE, or any other
garlic preparation, affects either NO production or action.
Aggregation of platelets is a consequence of exposure of fibrinogen
receptors on the surface of the cells. These receptors bind fibrinogen
in the presence of extracellular Ca2+ and
cross-link the platelets to form aggregates. The fibrinogen
receptor is a heterodimer of the membrane glycoproteins (GP)IIb and
IIIa, and although unstimulated platelets express the GPIIb-IIIa
complex at their surface, this complex is unable to bind fibrinogen
until platelets are activated, for example, by ADP (Hurani and Hall 1994
). The GPIIb-IIIa receptor has a high content of
-SH groups, and binding of fibrinogen is inhibited by the organosulfur
compound ajoene (Apitz-Castro et al. 1994
).
Steiner and Lin (1998)
suggested that the inhibition of
fibrinogen-mediated platelet adhesion is due to an organosulfur
compound(s) in dried AGE reducing the functional competence of some
GPIIb-IIIa receptors, whereas sufficient receptors remain
to sustain full ADP-induced aggregation. In contrast,
ADP-induced platelet aggregation was inhibited by the AGE
supplementation regimen used in our study (Fig. 1
, Table 1
). We
postulate that the most likely mechanism for this involves the ADP
receptor. Platelet ADP receptors belong to the
P2T subtype of purinoreceptors whose activation
leads to a rise in intracellular Ca2+. Thus, one
possibility would be that AGE inhibits the ADP-induced rise in
cytosolic Ca2+ concentrations. Indeed, aqueous
extracts of crushed garlic have been shown to inhibit the uptake of
Ca2+ into platelets (Mayeux et al. 1988
). Clearly, further studies are required to elucidate these
mechanisms.
In conclusion, our data clearly indicate that AGE, when taken as a dietary supplement, inhibits ADP-induced platelet aggregation in healthy subjects and may have a role in the prevention and management of cardiovascular disease.
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FOOTNOTES |
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3 Abbreviations used: AGE, aged garlic extract; ALT, alanine aminotransferase; EC50, median effective concentration; GP, glycoprotein; PG, prostaglandin; PPP, platelet-poor plasma; PRP, platelet-rich plasma; TX, thromboxane.
Manuscript received May 26, 2000. Revision accepted July 26, 2000.
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