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Advances in Medicinal Plant Research, 2007: ISBN: 81-7736-255-0
Editors: Surya N. Acharya and James E. Thomas
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Taking tomatoes to heart
A. K. Duttaroy
Department of Nutrition, Faculty of Medicine, University of Oslo, POB 1046 Blindern
N-0316 Oslo, Norway
Author
Dr. Asim K. Duttaroy is a Professor of Nutritional Medicine at the Department of Nutrition,
University of Oslo, Norway. His research focuses on identifying novel dietary means to reduce
type II diabetes, metabolic syndrome, and coronary heart disease; and to understand the
mechanisms behind the interactions between dietary factors and cell systems. His discovery of
anti-platelet factors in tomatoes has been patented internationally leading to the establishment of a
company, Provexis Limited in the UK (www.provexis.com). The product is being distributed by
Sircoheart. Dr. Duttaroy serves as an editorial board member of several journals and has published
135 scientific papers including reviews, book chapters and books.
Abstract
There is compelling evidence for tomatoes to be
considered as a cardiovascular protective food, due to
the presence of many nutrients which have been
associated with its perceived and/or proven effects on
the cardiovascular system. However, despite an
inverse association found for high intake of tomatobased products, dietary lycopene has not been
strongly associated with reduced risk of
cardiovascular disease (CVD). This indicates that
other unidentified compounds in tomatoes may have
Correspondence/Reprint request: Professor Asim K. Duttaroy, Department of Nutrition, Faculty of Medicine, University of
Oslo, POB 1046 Blindern, N-0316 Oslo, Norway. E-mail: a.k.duttaroy@medisin.uio.no
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A. K. Duttaroy
cardioprotective effects. We identified potent anti-platelet factors in tomato extracts,
which inhibited platelet aggregation. Platelets play a critical role not only in
haemostasis but also in the pathological development of cardiovascular diseases. There
is increasing evidence that acute clinical manifestations of coronary atherosclerotic
disease are caused by plaque disruption and subsequent platelet-thrombus formation.
Platelet activity can influence the progression of disease as well as the stability of
atherosclerotic plaques. We hypothesise that observed cardiovascular benefits attributed
to the tomato could be linked to antiplatelet activity and thus suppression of platelet
function in vivo. This type of natural anti-thrombotic agent could have an application in
primary prevention of CVD.
Introduction
During the last half-century, the fruit of the cultivated tomato (Lycopersicon
esculentum) has become a popular and highly consumed food (Canene-Adams et al.
2005). Tomato is a rich source of folate, vitamin C, and potassium (Blum et al. 2005;
Mancini et al. 1995). Tomato also contains several other components that are beneficial
to health, including vitamin E, trace elements, flavonoids, phytosterols, and several
water-soluble vitamins (Agarwal and Rao 2000; Mancini et al. 1995; Verhoeyen et al.
2002). Moreover, the antioxidant activity of lycopene as well as several other
carotenoids and their abundance in tomato, makes it a rich source of antioxidants
(Agarwal and Rao 2000; Mancini et al. 1995; Verhoeyen et al. 2002). In addition,
consumption of vitamin A precursors such as beta- and gamma-carotene present in
modest levels within tomato or tomato-based foods make this fruit rich in supply of
vitamin A activity.
Individuals in the Mediterranean area have a lower risk of several important chronic
diseases, including cardiovascular disease (CVD) and a number of types of cancer
(breast, colon, and prostate cancer) when compared with their North American and other
European counterparts (Agarwal and Rao 2000; Rissanen et al. 2002). These differences
may be associated with nutritional traditions. Consumption of tomatoes appears to be
one such tradition that may account for the lower risk associated with diseases in people
from this geographical area. In addition to vitamins and antioxidants, tomatoes also have
water soluble anti-platelet compounds, capable of inhibiting platelet aggregation both in
vitro and in vivo (Duttaroy et al. 2001). Therefore, presence of both antioxidants and
anti-platelet factors makes tomato a beneficial fruit in preventing CVD. There are
several excellent reviews available on the overall health benefits of tomatoes (Agarwal
and Rao 2000; Canene-Adams et al. 2005; Giovannucci 1999; Sesso et al. 2005;
Weisburger 2002; Willcox et al. 2003); however, this review will focus mainly on the
beneficial effects of tomatoes on cardiovascular health.
Epidemiology and intervention studies
There is epidemiological evidence that consumers of tomatoes have a lower risk of
many types of chronic diseases, including CVD and different forms of cancer (Agarwal
and Rao 2000; Cockey 2002; La 1998; Zackheim 1999). Evidence in support of the role
of lycopene in the prevention of CVD stems primarily from epidemiological
observations on normal and at-risk populations (Giugliano 2000; Maruyama et al. 2001;
Olfer'ev et al. 2004; Rao 2002; Rissanen et al. 2003). Geographic pathology has
Taking tomatoes to heart
3
produced important data which shows that populations with a regular intake of tomato
products, such as those found in the Mediterranean region, have a lower incidence of
chronic diseases in particular, CVD (Weisburger 2002). In recent epidemiological
studies, tissue and serum levels of lycopene, a carotenoid available from tomatoes, were
inversely related to the risk of CVD. Antioxidant properties of lycopene have been
suggested as being responsible for the beneficial effects of tomatoes and tomato-based
products (Agarwal and Rao 2000). Lycopene has been suggested to have several
mechanisms of action including inhibition of LDL oxidation (Heber and Lu 2002).
Lycopene is an open-chain hydrocarbon containing 11 conjugated and two nonconjugated double bonds arranged in a linear array. Lycopene, because of its high
number of conjugated dienes, is the most potent singlet oxygen quencher among the
natural carotenoids (Arab and Steck 2000). Although evidence for a relationship between
in vitro LDL oxidation and risk of CVD is not fully established, LDL oxidation is now
recognized as representing an important early event in the development of
atherosclerosis.
The strongest population-based evidence for the beneficial effects of lycopene
comes from a recently reported multi-centre case-control study (EURAMIC) that
evaluated the relationship between adipose tissue antioxidant status and acute
myocardial infarction. Subjects (662 cases and 717 controls) from 10 European countries
were recruited to maximize variability in exposure within the study. After adjusting for
age, body mass index, socioeconomic status, smoking, hypertension, and maternal and
paternal history of the disease, only lycopene, and not ß-carotene levels was found to be
protective against CVD (Kardinaal et al. 1993; Kardinaal et al. 1995; Kohlmeier et al.
1997). The protective potential of lycopene was maximal among individuals with the
highest polyunsaturated fat stores (Kardinaal et al. 1995). In a cross-sectional study
comparing Lithuanian and Swedish populations showing diverging mortality rates for
CVD, lower blood lycopene levels were found to be associated with increased risk and
mortality from CVD (Kristenson et al. 1997). In an Austrian stroke prevention study,
lower levels of serum lycopene and -tocopherol were reported in individuals from an
elderly population at high risk for microangiopathy-related cerebral damage (Schmidt et
al. 1997). Although the epidemiological studies conducted so far provide convincing
evidence for the role of lycopene in CVD prevention, it is at best only suggestive and not
proof of a causal relationship between lycopene intake and risk of CVD. Such proof can
be obtained only by performing controlled clinical dietary intervention studies where
both the biomarkers of the status of oxidative stress and the disease are measured. To
date, very few such intervention studies have been reported in the literature. In one
study, where healthy human subjects consumed a lycopene-free diet for a period of 2
weeks, their serum lycopene levels decreased by 50% by the end of week 2 and, at the
same time, an increase of 25% in in vivo lipid oxidation was observed (Allen et al.
2003). In a small dietary supplementation study, six healthy male subjects consumed 60
mg/day lycopene for 3 months (Fuhrman et al. 1997). At the end of the treatment period,
a significant 14% reduction in their plasma LDL cholesterol levels was observed
(Fuhrman et al. 1997). In a randomized, crossover dietary intervention study, 19 healthy
human subjects (10 male and 9 female), non-smokers, not on any medication and
vitamin supplements, consumed lycopene from traditional tomato products and
nutritional supplements for 1 week. Although there were no changes in serum total
4
A. K. Duttaroy
cholesterol and LDL and HDL cholesterols, serum lipid peroxidation and LDL
cholesterol oxidation were significantly decreased as the serum lycopene levels
increased (Agarwal and Rao 1998). However, despite an inverse association found for
high intake of tomato-based products, dietary lycopene was not strongly associated with
the risk of CVD. This indicates that other unidentified compounds in tomatoes may have
cardio-protective effects.
Beneficial effects of tomatoes on the cardiovascular system
a. Atherosclerosis
Although genetic factors and age are important in determining risk, several other
factors, including hypertension, hypercholesterolemia, insulin resistance, smoking and
diet are also major risk factors associated with CVD (King 2005; Pearson et al. 2000;
Roche et al. 2005; Tai and Tan 2005). Oxidative stress induced by reactive oxygen
species (ROS) is also considered to play an important role in the aetiology of several
chronic diseases, including CVD (Jialal and Fuller 1993; Molavi and Mehta 2004;
Nuttall et al. 1999). Oxidation of circulating LDLs that carry cholesterol into the blood
stream to oxidized LDL is thought to play a key role in the pathogenesis of
atherosclerosis, which is the underlying disorder leading to heart attack and ischaemic
strokes (Jialal and Fuller 1993; Molavi and Mehta 2004; Nuttall et al. 1999). Antioxidant
nutrients are believed to slow the progression of atherosclerosis because of their ability
to inhibit damaging oxidative processes. Lycopene is one such dietary antioxidant that
has received much attention recently. Other possible mechanisms include enhanced LDL
degradation, LDL particle size and composition, plaque rupture, and altered endothelial
functions. However, there is convincing evidence to indicate that ROS generated both
endogenously and also in response to diet and lifestyle factors may play a significant role
in the aetiology of atherosclerosis and CVD. Central to this oxidative hypothesis is
oxidation of LDL as the primary initial step leading to its uptake by macrophages inside
the arterial wall and, formation of foam cells and atherosclerotic plaque. LDL consists of
a large molecular weight-protein, apolipoprotein B, neutral and polar lipids and, a
mixture of lipophilic antioxidants including ß-carotene and vitamin E. As a result of
oxidative modifications of the native LDL molecule, several biologically active
molecules can be formed, including protein adduct products with breakdown products of
oxidized fatty acids that facilitate recognition of modified LDL by macrophage
scavenger receptors. In addition to influencing the formation of foam cells and plaque in
arterial walls, components of oxidized LDL (oxLDL) can also influence other events that
are related to increased risk of CVD. These include their ability to: increase cholesterol
accumulation by macrophages; produce proteins that are chemotactic to monocytes and
cytotoxic to a variety of cells causing endothelial injury; alter gene expression in arterial
cells leading to increased expression of colony-stimulating factors; increase expression
of adhesion molecules at the endothelial cell surface; inhibit an endothelium-dependent
relaxation factor and promote vasospasm; inhibit vasodilatation; increase binding to type
1 collagen and; enhance coagulation pathways and platelet aggregation. In addition,
oxidised components of LDL can promote migration and proliferation of smooth muscle
cells, formation of foam cells and fatty streaks in the arterial intima and, cause eventual
rupture of arterial plaques. Therefore, inhibition of LDL oxidation may play an
important in preventing CVD.
Taking tomatoes to heart
5
Some 725 middle-aged men, free of coronary heart disease and stroke, took part in a
Kuopio Ischemic Heart Disease Risk Factor (KIHD) study. Men within the lowest
quartile for serum levels of lycopene had a 3.3 fold increased risk of an acute coronary
event or stroke as compared to other groups within the study (Rissanen et al. 2001). In a
second study, association between plasma lycopene concentration and intima-media
thickness of the common carotid artery wall (CCA-IMT) was examined (Rissanen et al.
2003). This research was part of an Antioxidant Supplementation in Atherosclerosis
Prevention (ASAP) study, in which 520 asymptomatic men and women participated
(Rissanen et al. 2000). It was found that low plasma levels of lycopene in men were
associated with an 18% increase in IMT when compared with men whose plasma levels
were higher than the median. In women, this difference was not significant (Rissanen et
al. 2000; Rissanen et al. 2003).
A number of in vitro studies have shown that lycopene can protect native LDL from
oxidation and can suppress cholesterol synthesis. In a J-774 A.1 macrophage-like cell
line, lycopene treatment at a concentration of 10 µM, produced a 73% inhibition in
cholesterol synthesis using [3H]acetate as a precursor (Fuhrman et al. 1997). A slightly
lower inhibition of cholesterol synthesis was also observed with ß-carotene. In this
study, both of these carotenoids augmented the activity of the macrophage LDL receptor.
However, in another study, dietary enrichment of endothelial cells with ß carotene but,
not lycopene inhibited the oxidation of LDL (Dugas et al. 1999). Predictability of in
vitro LDL oxidation as a marker of atherosclerosis or coronary heart disease has been
questioned in recent years. In animal intervention studies where an increase in resistance
of extracted LDL to in vitro oxidation was shown to occur, correlation to a reduced risk
of atherosclerosis was not always observed. Use of well-defined subject populations,
standardized outcome measures of oxidative stress and disease, and lycopene ingestion
that is representative of a normal healthy dietary intake is essential for development of a
meaningful interpretation of the results in terms of therapeutic applications. Some of the
conflicting epidemiological observations being reported in the literature may be
connected to issues related to lycopene absorption. In general, circulating and adipose
tissue levels of lycopene seem to be better indicators of disease prevention than dietary
intake data. Lycopene has been shown to be absorbed better from processed tomato
products than from fresh tomatoes. Careful consideration must be given to all of these
factors in designing future studies to evaluate the role of lycopene in the prevention of
CVD.
b. Platelet function
Platelet aggregation is fundamental to a wide range of physiological and pathological
processes, including the induction of thrombosis and arteriosclerosis (Duttaroy et al. 1989;
Hamet et al. 1983; Kroll and Schafer 1989). Normal haemostasis is initiated when platelets
are exposed to the sub-endothelial matrix, where they adhere to collagen via specific cellsurface receptors (Coller et al. 1995; Dutta-Roy et al. 1986; Kroll and Schafer 1989). This
adhesion step is followed by platelet activation that is accompanied by synthesis and
release of pro-aggregatory molecules such as thromboxane (Tx) A2 and ADP, which
amplify platelet responses to collagen and recruit additional platelets to the site of injury
(Coller et al. 1995; Duttaroy et al. 1986; Kroll and Schafer 1989). The concerted action of
collagen, ADP, and TxA2 activates specific signalling pathways, generating a number of
6
A. K. Duttaroy
second messengers and leads to functional expression of a GPIIb-GPIIIa complex of the
fibrinogen receptor on the platelets (Coller et al. 1995; Duttaroy et al. 1986; Kroll and
Schafer 1989). Pro-haemostatic mechanisms appear to be counterbalanced and regulated
by a number of physiologic anti-haemostatic molecules that work in a concerted and
redundant manner, resulting in the release of prostacyclin (PGI2), nitric oxide, and
endothelium-dependent hyperpolarizing factor by the endothelium as well as ADP
hydrolyzing activity associated with endothelial cell membrane apyrase (CD39) (Duttaroy
et al. 1991; Duttaroy 1994; Duttaroy and Sinha 1987; Harker and Fuster 1986).
Aggregation of platelets by agonists is mediated, in part, through the intracellular
formation of prostaglandin (PG) G2, PGH2 and TxA2 from arachidonic acid, 20:4n-6
(AA) (Duttaroy et al. 1991; Duttaroy 1994). In contrast, PGI2, an arachidonic acid
metabolite of endothelial cells, is the most potent natural inhibitor of platelet aggregation
(Duttaroy et al. 1991; Duttaroy 1994). Prostaglandin-induced inhibition of platelet
aggregation is mediated through an increase in cAMP synthesis due to activation of
adenylate cyclase. Activation of adenylate cyclase is initiated by binding of PGI2 or PGE1
to specific platelet surface receptors. Alternatively, cAMP levels in platelets can also be
increased by inhibiting cAMP phosphodiesterase activity (Duttaroy and Sinha 1987).
Hyperactivity of platelets and, their adhesion and aggregation at the site of injury in
atherosclerotic vessel walls, is critically important to the pathogenesis of CVD (Duttaroy
et al. 1986; Duttaroy 1994; Hamberg et al. 1974; Hamet et al. 1983). Furthermore, there
is increasing evidence that acute clinical manifestations of coronary atherosclerotic
disease are caused by plaque disruption and subsequent platelet-thrombus formation
(Badimon et al. 1999; Falk et al. 1995). Coronary atherosclerotic lesions appear in early
life and towards the end of the second decade of life; asymptomatic atherosclerosis
lesions are present in most people living in industrialised societies. Platelet activity is
thought to play a major role in the development as well as, in the stability of atherosclerotic
plaques (Badimon et al. 1999; Falk et al. 1995). In support of the pathophysiological role
of platelets, platelet inhibitory drugs such as aspirin have been observed to reduce the
incidence of myocardial infraction, stroke and death from cardiovascular disease in
secondary prevention trials (Schror 1997). However, the anti-platelet effects of aspirin are
actually relatively weak and, the drug also has been shown to cause severe gastrointestinal
disturbances and bleeding problems in some patients. Given the high incidence of
cardiovascular disease in developed countries, there is great need for identification of
effective anti-platelet compounds. These should inhibit platelet aggregation without
increasing bleeding time (a problem associated with glycoprotein IIb/IIIa antagonists) in
order to circumvent problems with ulcers in patients who are taking aspirin as a
prophylaxis (Schror 1997). Recently, aspirin’s anti-platelet limitations have progressively
underscored the critical need for improved platelet aggregation inhibitor therapy which is
not only effective, but also safe and well tolerated. This concept has stimulated research
into prevention of platelet hyperactivity by several means including dietary
supplementation (Duttaroy et al. 1999; Duttaroy 2002; Pierre et al. 2005).
Effects of different fruit extracts on human platelet
aggregation in vitro
We have demonstrated the presence of anti-platelet factors in tomatoes (Duttaroy et
al. 2001; Duttaroy 2002). Table-1 shows the inhibitory effect of different fruit extracts
Taking tomatoes to heart
Table 1. Effects of fruit extracts on inhibition of platelet aggregation in humans.
on human platelet aggregation in vitro. The maximum inhibitory effect (70-75%) was
found to be with tomato and kiwi fruit extracts whereas, apple and pear had very
little activity (2-5%). Grapefruit, melon and strawberry had intermediate activities on
platelet aggregation (33-44%). The pH of the different fruit extracts was acidic in
nature; therefore the pH of our extracts was adjusted to pH 7.4 in order to avoid any
effect of acidic pH on the platelet aggregation response. With the exception of
avocado, apple, nectarine, banana and mango, a 100% juice (w/v) extract was used.
A dose–dependant inhibition of platelet aggregation was observed for the tomato
extract; maximum inhibition (72%) was obtained when 50 µl (100% juice) of tomato
extract was added to 500 µl of prepared platelets. Most of the anti-platelet properties
of tomatoes reside in the juicy part of the fruit. The anti-platelet potential of the
fruits tested appeared to be opposite to that of their antioxidant activity which was
reported earlier by Wang et al. (1996). According to the these authors, strawberry
had the highest antioxidant capacity followed by plum, orange, red grape, kiwi fruit,
pink grapefruit, white grape, banana, apple, tomato, pear, and honeydew melon.
Since the anti-platelet activity in fruits is quite different from their antioxidant
properties, it is possible that these activities are due to the presence of compounds
that have a different chemical structure. Tomato extract used in a dose-dependant
manner inhibited ADP-induced platelet aggregation; i.e., 25 µl of tomato extract
(100% juice) inhibited platelet aggregation by 63% compared with the control
whereas, 50 µl of tomato extract (100% juice) inhibited 75% of collagen-induced
platelet aggregation in a 500 µl assay. The IC50 (minimum concentration required
for 50% inhibition of platelet aggregation induced by ADP in 500µl PRP) of tomato
extract was around 20µl (100% juice). The tomato and kiwifruit extract inhibited
both collagen-and ADP-induced platelet aggregation to a similar extent but, could
not inhibit arachidonic acid-induced aggregation and thromboxane synthesis.
7
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A. K. Duttaroy
Further characterisation of anti-platelet factors in tomato
extract
Delipidation of the tomato ultrafiltrate (100,000 x g) obtained from the tomato
extract demonstrated that the anti-platelet factor(s) were not lipid-soluble compounds.
The delipidated aqueous fraction was further purified by gel filtration using a Bio gel P2
column (Figure-1). Among several peaks that emerged from the column, peaks- 3 and -4
showed high anti-platelet activity. Figure-2 shows the inhibitory effect of tomato extracts
(peak-3 and peak-4) on whole blood aggregation induced by ADP. Peak–4, when
subjected to HPLC using an anion ion exchange column, resolved into several peaks.
Figure-2 shows the anti-platelet activity for peak 3 and peak-4 in whole blood
aggregation. Maximum anti-platelet activity was associated with F2. However, the
pooled fraction (F1) eluted prior to F2, also had some anti-platelet activity. Like peak-4
and peak-3, F2 had a similar inhibitory effect against ADP (79-87% inhibition) and
collagen–induced platelet aggregation (60-97%) when incubated with PRP for 10 min.
These tomato fractions inhibited TXB2 synthesis in response to ADP or collagen (almost
57-97% inhibition compared with the control) but, could not inhibit its synthesis when
arachidonic acid was used. This indicates that the active components present in tomatoes
inhibit platelet aggregation without involving the thromboxane pathways (the
cyclooxygenase system). Since adenosine is a platelet inhibitor, the anti-platelet activity
of tomato extract or tomato-derived components could be due to the presence of
adenosine. In order to examine whether there were other components apart from
adenosine responsible for inhibition of platelet function, samples of tomato extracts from
peak-3, peak-4 and F2 were deaminated and then, their effect on platelet aggregation
was determined (Figure-3). Adenosine deaminase, at a final concentration of 8U/ml,
was effective at deaminating adenosine (4mg/ml), decreasing its effectiveness as an
anti-platelet agent from 61% to 7% inhibition in ADP-induced platelet aggregation.
Figure 1. Purification scheme of tomato extract: Tomato extract was centrifuged at 110,000xg for
30 min, then the supernatant was ultrafiltered through the membrane filter (Mw cut-off, 1000da).
The ultrafiltrate was delipidated using the Lipidex 1000 method. The delipidated material was then
chromatographed on a bio gel P2 column. Nine peaks were eluted and, peak (P3), and peak-4 (P4)
were found to be effective in inhibiting platelet aggregation. Peak 4 contained adenosine and
cytosine as analysed by NMR whereas, peak-4 compounds are yet to be analysed.
9
Taking tomatoes to heart
Control
125
Peak 3 (25ul)
% whole blood aggregation
Peak 4 (25ul)
100
75
50
25
0
0.0
2.5
5.0
7.5
10.0
12.5
Time (mins)
Figure 2. Effects of tomato extract on whole blood aggregation induced by collagen. Whole blood
was incubated with peak-3 or peak-4 for 10 min. before collagen (1µM) was added to initiate
aggregation. Control (- -), Peak-3 (-z-), Peak-4 (- o -).
% Inhibition of platelet aggregation
100
90
80
70
60
50
40
30
20
10
0
A
DA
P-3
DP-3
P-4
DP-4
P-F2
DP-F2
Tomato extracts
Figure 3. Effect of deaminated tomato extract on ADP-induced platelet aggregation where, A =
Adenosine; DA = Deaminated Adenosine; P =Peak; DP = Deaminated Peak. Platelet aggregation
response to ADP was measured after incubating 450 ml platelet rich plasma (PRP) with 20 ml of
the tomato fractions and adenosine (with or without deamination). For details please see Duttaroy
et al. 2001.
Deamination of adenosine was evident from the disappearance of an adenosine peak and
appearance of inosine in our assays. The deaminated F2 sample showed a complete loss
of adenosine and also anti-platelet activity whereas, deaminated peak-4 inhibited ADPinduced aggregation by 50% compared to 94% for the untreated peak-4 (p<0.01); the
anti-platelet activity of peak-3 was unaffected by adenosine deaminase treatment under
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A. K. Duttaroy
similar experimental conditions. These data indicate that tomato juice contains antiplatelet compound (s) other than adenosine. When inhibition of thrombin-induced
platelet aggregation by adenosine, aspirin and tomato extracts was examined, only
tomato extract inhibited thrombin–induced platelet aggregation and this inhibition was as
high as 99% in some cases.
These anti-platelet compounds in tomato, had a molecular mass less than 1000da,
were highly water soluble and were stable after boiling. In addition to adenosine, tomato
extract has other anti-platelet compounds (that were not destroyed by adenosine
deaminase treatment, and that had anti-thrombin activity); however, their structure is yet
to be determined. In addition to its anti-platelet property, adenosine modifies several
important cellular processes in the cardiovascular system; i.e., it relaxes vascular smooth
muscle, inhibits both the aggregation of platelets and the generation of superoxide anions
by neutrophils and, prevents adhesion of neutrophils to the endothelium. Various
physiological effects of adenosine act synergistically to maintain coronary blood flow
and to attenuate myocardial injury due to ischemia and reperfusion. Tomato extract, by
virtue of its adenosine content, may also synergistically inhibit thrombin-induced platelet
aggregation by other inhibitors.
The thromboxane pathway does not appear to be involved in tomato extract
inhibition of platelet aggregation. This is quite different than that of aspirin.
Aspirin’s anti-platelet action involves inhibition of the cyclooxygenase enzyme in
platelets, leading to decreased formation of prostaglandin G2, a precursor of TxA2
and thus, blocking the formation of TxA2, a platelet aggregation agonist. Since
tomato extract or the fractions derived from it, do not inhibit the thromboxane
pathway, it is possible that their mode of action is upstream of the platelet
activation/aggregation processes but, not of thromboxane synthesis. Adenosine
raises the level of cAMP in platelets; however, it does not inhibit thrombin-induced
platelet aggregation by itself. The anti-platelet agents in tomatoes, however, may
work as direct inhibitors of thrombin, as fibrinogen-receptor antagonists, or as
specific inhibitors of collagen- and ADP-induced platelet aggregation. Further work
using purified compounds isolated from tomato is required in order to understand
which of the above steps are affected in the activation of platelets.
So, despite aspirin’s inhibition of TxA2, platelets may be induced to aggregate by
other triggers such as thrombin – the most potent agonist of platelet aggregation.
However, tomato-derived compounds also inhibit thrombin-induced platelet aggregation.
Anti-thrombotic properties of tomato have been demonstrated in a rat model (Yamamoto
et al. 2003). Recently, we completed two trials using tomato extracts in humans
volunteers (O’Kennedy et al. 2006a; b). A significant reduction in platelet aggregation
induced by both ADP and collagen was observed at 3h after consuming tomato extract
(O’Kennedy et al. 2006a; b).
In conclusion, tomato extracts or derived products may equally be effective at
inhibiting platelet aggregation induced by collagen, ADP and thrombin. Our data
provides evidence that tomato extracts have great potential for increasing the
effectiveness of thrombosis prophylaxis through an oral tomato extract therapy.
Modulation of platelet reactivity towards collagen, ADP and thrombin by tomato extract
could be of potentially prophylactic and therapeutic benefit in preventing and halting
pathologic processes that lead to CVD.
Taking tomatoes to heart
11
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