Journal of the Science of Food and Agriculture J Sci Food Agric 86:1805–1813 (2006)

Review
A review of the health care potential
of bioactive compounds
Lee Hooper and Aedin Cassidy∗
School of Medicine, University of East Anglia, Norwich, NR4 7TJ, UK

Abstract: The projected incidence of chronic disease and the importance of diet in potentially reducing this
risk require urgent attention. Current health care systems will be unable to cope with the increased incidence of
cardiovascular disease, diabetes and cancer, particularly with the ageing population and global increased incidence
of obesity. There is growing interest in bioactive compounds present in plants and their potential importance
in reducing risk of chronic disease, and these data will be reviewed with particular focus on flavonoids, sterols,
salicylates and glucosinolates
 2006 Society of Chemical Industry

Keywords: stanols; sterols; isoflavones; flavonoids; salicylates; glucosinolates; lignans

INTRODUCTION health perspective are the flavones, flavonols, flavan-

Compelling epidemiological evidence is available 3-ols, isoflavones, flavanones and anthocyanidins, and
on the benefits of consuming diets rich in plant- lignans (Fig. 1). Current estimated daily intake of
based foods, with current advice for optimal health flavonoids is greater than 50 mg, and realistically
suggesting high consumption of a plant-based diet.1 intake is higher than 100 mg d−1 if data on all
Although to date most research on the health benefits flavonoid groups were available. If this intake is
of plant-rich diets has focused on the established compared to daily intakes of established vitamins
vitamins, the available data are not convincing and (vitamin C (80 mg d−1 ), vitamin E (8.5 mg d−1 ) and
the drive continues to identify other additional β-carotene (1.9 mg d−1 ), it is clear that flavonoid
components of a healthy diet which may reduce intakes exceed or are at least comparable to these,
the risk of chronic disease. In primary prevention, providing strong evidence that these compounds
diet is the preferred treatment option for some constitute an important part of dietary intake of
conditions, including early type 2 diabetes and biologically active compounds. Over the last few years
hypercholesterolaemia, despite the widespread use and there have been major advances in our understanding
effectiveness of drug therapy like statins.2,3 Given the of the absorption and metabolism of many of the
prevalence of people with high risk for chronic diseases flavonoid subclasses, and for some subclasses sufficient
like cardiovascular disease, a prevention strategy based levels are absorbed to have the potential to exert
on drug therapy is not sustainable on the National biological effects; for example, isoflavones following
Health Service; if current guidelines were followed, soya consumption, catechins after wine consumption
>25% of all middle-aged Scottish men would be and quercetin following consumption of onions can
prescribed cholesterol-lowering drugs and, given the reach micromolar concentrations in the blood.5 – 9
success of statins in reducing all-cause mortality in These data suggest that these compounds have the
normo-cholesterolaemic subjects, this would further potential to exert biological effects in vivo as they can
increase the proportion of the general population for cross the intestinal barrier and reach concentrations
whom a statin may be recommended.4 that have been shown to be biologically active
Plant foods contain an array of bioactive compounds in vitro.10
which are actively being researched for their health care Promising data from epidemiological studies and
potential, including flavonoids, plant sterols/stanols, in vitro data suggest that diets high in flavonoids
salicylates and glucosinolates. potentially reduce the risk of chronic disease, and
numerous intervention trials attest to the significant
biological effects of flavonoids in humans.10
Polyphenols
Several thousand different polyphenols exist which Flavonols
can be subdivided into different subclasses. The Common flavonols include quercetin, kaempferol and
main subclasses that are important from a human myricetin, and they occur in higher levels in onions,

∗
Correspondence to: Aedin Cassidy, School of Medicine, University of East Anglia, Norwich, NR4 7TJ, UK
E-mail: a.cassidy@uea.ac.uk
(Received 21 November 2005; revised version received 11 January 2006; accepted 15 June 2006)
Published online 3 August 2006; DOI: 10.1002/jsfa.2599

 2006 Society of Chemical Industry. J Sci Food Agric 0022–5142/2006/$30.00

L Hooper, A Cassidy

OH
OH
OH
HO O
HO O

OH
OH O
OH
Epicatechin Naringenin

Flavan-3-ol Flavanone

OH
OH OH

HO O HO O

OH
OH O
OH O
Quercetin Apigenin

Flavonol Flavone

HO O
HO O

OH O HO OH
OH
Genistein OH
Gallic Acid

Isoflavone ProAnthocyanidin

Figure 1. Structures of the major subclasses of flavonoids.

Table 1. Principal dietary sources of flavonoids

Flavonoid Compound Food source

Flavonol Quercetin, kaempferol, myricetin Onion, apple, broccoli, tea, olives, kale, cranberry, lettuce,
beans (green, yellow)
Flavone Luteolin, apigenin Olives, celery
Flavan-3-ol Catechin, epicatechin Tea, red wine, apple
Flavanone Naringenin, hesperidin Citrus fruit
Anthocyanidins Cyanidin, delphinidin, malvidin, petunidin Grapes, cherries
Chalcones, dihydrochalcones Heavily hopped beer, Tomatoes (with skins), cider, apple
juice
Isoflavone Genistein, daidzein Soy

Source information: Hollman and Katan (1997);8 Scalbert and Williamson (2000).8

apples, tea and kale. There is limited consistent known as flavan-3-ols or catechins. They are found in
evidence to support a potential effect of quercetin on many plant foods, notably tea, red wine and apples
health from in vivo studies, although this may relate to (Table 1). Catechin levels are particularly high in
the short-term nature of the studies and the biomarkers broad beans, black grapes, strawberries and apricots;
assessed in the available studies.10 epicatechins are present in high concentrations in
apples, blackberries, chocolate and pears. The gallates
Catechins and gallocatechins are found almost exclusively in tea,
The principal flavanols include catechin, epicatechin especially green tea. Given the range of concentrations,
and gallocatechin. These compounds are often found and because the non-galloylated forms are widespread,
as esters with gallic acid and are known as epicatechin it is difficult to estimate the daily consumption of these
gallate and epigallocatechin gallate. Flavanols are also compounds.

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 Health care potential of bioactive compounds

In human intervention feeding trials with 1–2 µmol L−1 .14,15 These flavanone aglycones have
monomeric catechins, plasma levels of the order of also been shown to be degraded by human and animal
0.1–0.5 µmol L−1 were attained, which were rapidly intestinal microflora to simpler phenols and phenolic
cleared. Catechins have been shown to increase acids.
plasma antioxidant activity, decrease plasma lipid In the hypercholesterolaemic hamster, the combina-
peroxide and malondialdehyde concentrations, and tion of a flavonone-rich citrus extract and ascorbic acid
increase resistance of low-density lipoprotein (LDL) decreased lipids and other lipid-related factors related
to oxidation.10 to atherosclerosis.16 In colon cancer-induced rats, the
flavonone hesperidin has been shown to decrease the
Procyanidins incidence of tumours and inhibit the development of
Procyanidins are oligomeric catechins covalently aberrant crypt foci.17
linked together. They are present in high levels in
cocoa, grapes, wine, apples and other fruits, includ- Isoflavones
ing blackberries and plums. The metabolic fate Isoflavones are flavonoids, but are also called phytoe-
of procyanidin is still not clear, with studies sug- strogens and to date are the most researched class
gesting low measurable levels in blood following of the polyphenols. Phytoestrogens are multifaceted
procyanidin-rich foods; following consumption of 2 g compounds which have been extensively reviewed,
high-procyanidin grapeseed extract, plasma levels of with a recent review appraising the results of all
procyanidin reached only 10 nmol L−1 ,11 and con- human intervention studies in relation to menopausal
sumption of cocoa resulted in plasma concentrations of health;18 – 20 however, to date much of the interest
41 nmol L−1 .12 However, given that biological effects in their biological activity has related to potential
have been observed in some intervention studies, the health effects in menopausal women. The interna-
effects are either attributable to currently unidenti- tional variation in cardiovascular disease, osteoporosis,
fied metabolites (for example, gut metabolites) or are menopausal symptoms, breast and prostate cancer has
attributable to another component of the foods con- stimulated interest in the role of isoflavones in the diet
sumed. Most studies examining effects of procyanidin as potentially protective components. In Asia, where
have investigated potential effects on the vascular urine and plasma levels of isoflavones are high, these
system and include an observed increase in plasma conditions are rare.21 However, to date, clinical stud-
antioxidant potential, decreased platelet aggregation, ies that have examined the potential of isoflavones to
decreased LDL levels and decreased levels of lipid cause physiological effects in humans have been lim-
peroxide.10 ited to epidemiological studies, or to dietary interven-
tion trials that have examined effects on menopausal
Anthocyanins symptoms, cardiovascular function and endocrine reg-
Anthocyanins have been identified in over 27 families ulation of the menstrual cycle. Overall, these dietary
of food plants, and in the USA the consumption has studies have shown effects that may be interpreted as
been estimated at 215 mg during summer and 180 mg beneficial, but it is difficult to tease out the precise con-
during winter. In Finland, intake has been estimated tribution that isoflavones play in the overall endpoints
to be 82 mg d−1 , with the main source being berries, measured.
red wine and juices. Anthocyanins are present in large The well-publicized results of two large-scale
amounts in some foods; for example, a serving of hormone replacement therapy (HRT) trials – the
200 g of aubergine or black grapes can provide up Women’s Health Initiative in the USA and the
to 1500 mg and servings of berries up to 500 mg. Million Women’s study in the UK showing evi-
Human data on the absorption and metabolism of dence of an increased risk of combined HRT on
anthocyanins suggest that levels attained in plasma are breast cancer, heart disease, stroke and venous
very low, of the order of 10–50 nmol L−1 ,13 but the thromboembolism22,23 – have led to the conclu-
methods used may not have been optimized to assess sion that HRT will not protect future health,
all metabolites. Given the analytical limitations and although short-term use remains beneficial for severe
lack of research in this area, not much can be said menopausal symptom relief.24 Since the justification
about the health benefits of these compounds. for long-term HRT can no longer be applied for dis-
ease prevention, women continue to seek alternative
Flavanones ‘natural’ options, like phytoestrogens, to improve their
Flavanones are commonly found in citrus fruits. quality of life and reduce their risk of disease, but many
Examples include hesperetin (lemon, lime and man- are unaware of the limited scientific evidence of safety
darin) and naringenin (grapefruit). These compounds and efficacy of such natural therapies
are found in higher concentrations in the skin of the Traditionally, phytoestrogens have been considered
fruits than the flesh or juice. In human studies total to be weakly oestrogenic and it is well established
urinary excretion of conjugated flavanones accounted that serum levels of isoflavones following consumption
for 8.6% of hesperetin intake and 8.8% of naringin.13 of a modest intake of soya foods can reach the
Following consumption of orange juice levels (con- low micromolar level, about 100–1000 times that
taining 130–200 mg) hesperetin metabolites reached of oestradiol. Therefore, even if these compounds

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L Hooper, A Cassidy

have a weak potency, they have the potential to exert is not uncommon, with intake levels ranging from
biological effects in vivo and such effects have been 32 to 66 mg aglycone equivalents in several recent
reported in several trials using a range of different studies.37 – 39 The most widely used soya products,
endpoints.25 – 29 Although all soya protein extracts soya oil, soya sauce, and soya lecithin, do not have
and foods available for human consumption contain significant levels of isoflavones, and this is also the
significant levels of isoflavones, there is large variability case for aqueous alcohol-washed soya proteins.30
in concentration and profile among these products that Knowledge of the pharmacokinetics of phytoestro-
depends on species, geographical and environmental gens is essential prior to making recommendations
conditions, and the extent of industrial processing of regarding long-term efficacy in clinical studies, as
the soya beans.30 However, even for a given brand of recent research suggests significant differences in
soya product, recent data suggest significant variation bioavailability between foods rich in phytoestrogens
in isoflavone levels over time.31 and supplements.40,41 In addition, the dose adminis-
There are numerous commercial phytoestrogen tered, food matrix and chemical form of the compound
supplements available, which are predominantly appear to exert effects on the bioavailability.41 Mainte-
promoted for their value in treating postmenopausal nance of a steady-state serum level should be optimal
conditions. These are made from a variety of for clinical effectiveness of these compounds, and on
sources, including concentrated soya bean extracts, the basis of current pharmacokinetic data this would
or an extract of red clover. However, to date be best achieved by divided doses of the soya food
there are limited data examining the relative clinical or supplement throughout the day, rather than by a
effectiveness of specific preparations, and analytical single dose. The available absorption and metabolism
data suggest that quality assurance is a significant issue data for these compounds suggest that levels attained
with commonly available isoflavone supplements.6 in plasma do not increase in a linear fashion with
In general, Western populations consume low levels increased intake,40,41 suggesting limited advantage in
of isoflavones because few foods included in the consuming high levels of these compounds through
typical Western diet contain soya protein, the fraction functional foods and supplements, but data on the
with which isoflavones are associated. The average levels attained in plasma following mega-dosing of
daily dietary intake of isoflavones among Western these compounds warrant further investigation.
populations is negligible (<1 mg d−1 )18 and the lack
of these dietary phytoprotectants is viewed as one
explanation for the disparity in disease incidence rates Stilbenes
between Western and Asian populations. Stilbenes are present in a wide range of plant and
Soya has been a traditional staple in Far Eastern are synthesized from cinnamic acid derivatives. Their
countries for generations, and the lower incidences of production in plants is positively associated with
osteoporosis, breast cancer and menopausal symptoms resistance to mould and is produced in response
among women who consume soya as a dietary to microbial infection or stress. Trans-resveratrol
staple have been suggested to be due in part to has been identified as the major active component
the high intake of isoflavones.21,32,33 In the early and most studies to date have concentrated on the
1990s estimates of intakes in Asian countries were physiological effects of this stilbene.
in the region of 100 mg isoflavones per day but these In folk medicine, including Chinese medicine,
data are now acknowledged as overestimates. As the humans have used medicinal plants containing
methods of analysis of levels in foods have been resveratrol for many years. Based on the quantitative
improved, there has been a move towards a consistent data currently available, the major dietary sources
form of reporting of intake in aglycone equivalents of stilbenes are grapes, grape juices, wine, peanuts
(converted from glucosides using the appropriate and peanut butter. They are predominantly located in
ratios of molecular weights). More recent estimates the skin and in general are absent, or present in low
of the amounts of soya food consumed in Japan amounts, in fruit flesh and are produced in response to
indicate typical isoflavone intakes of 11–40 mg d−1 stress.8 In wines the levels of resveratrol depend on the
(reported as aglycone equivalents to standardize doses grape variety, climatic conditions of the harvest and
between different foods) in adults.34,35 This would the ecological procedures employed; however, studies
convert to 18–63 mg d−1 as the glucoside, using suggest that the levels in red and white grape skins are
1.61 as the conversion factor based on the ratios of comparable. It is the extent of maceration of skins and
genistein, daidzein and glycitein in the most commonly seeds during fermentation that is the key determinant
consumed foods.36 However, it is difficult to determine of the stilbene concentration in the wine, but the
the precise isoflavone intake in countries such as yeast strains used, the fining agents used and the
China, Korea, Indonesia and Japan. Food and eating time spent in oak barrels also alter levels. Red wines
trends are changing rapidly, intake levels may vary contain the highest levels of trans-resveratrol, with
between urban and rural areas, and intake is affected by approximately 8 mg L−1 , but levels vary depending on
generational and lifestyle differences. However, data the grape variety. Levels in rosé wines range between
from several studies suggest that intakes of 60 mg 1.38 and 2.93 mg L−1 , while levels in white wines are
isoflavones (expressed aglycone equivalents) per day generally low since during the wine-making process

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 Health care potential of bioactive compounds

minimal contact is made with the grape skins, which isoflavones, the lignans undergo efficient enterohep-
are the main source of resveratrol. atic circulation; they are absorbed from the intestinal
In vitro resveratrol has been shown to inhibit LDL tract and transported via the portal vein system to
oxidation and inhibit platelet aggregation; in human the liver, where they undergo conjugation with glu-
endothelial cells, resveratrol induced vasorelaxation curonic acid. This more water-soluble conjugate is
and reduced thrombogenic potential, by inhibiting then excreted via the kidneys and by the biliary route,
expression of adhesion molecules.42 – 44 Resveratrol has where it is present primarily as the non-glucuronide
also shown potential anticancer activity with in vitro conjugate in urine and bile.
evidence to show its ability to inhibit cancer initiation Epidemiological studies have shown positive corre-
and promotion.42 lations between intake of fibre-rich foods and urinary
lignan excretion. This is not surprising given the richest
dietary sources of lignan precursors (pulses, legumes,
Salicylates
fruit, vegetables). To date there have been several ani-
There is growing interest in the potential role of dietary
mal studies addressing the potential anticancer effects
salicylates in disease prevention, as the clinical efficacy
of these compounds, but to date interest in the bio-
of pharmacological salicylates such as acetylsalicylic
logical effects of lignans in relation to human health
acid (aspirin) in the treatment of human disease has
has received little attention compared to the isoflavone
been well recognized for many years.45 Salicylic acid is
class.
synthesized by plants as part of the systemic acquired
resistance response to pathogen attack and, until
recently, it has not been clear whether there is sufficient Stanols and sterols
bioavailable salicylic acid in plant-based foods to Plant sterols and stanols are similar in structure to
exert protective effects. However, it has recently been cholesterol (Fig. 2), but unlike cholesterol are not
observed that salicylic acid is present in a wide synthesized in humans. Normal dietary intake of
variety of fruit, vegetables, herbs and spices of dietary plant sterols in the Western world is 100–400 mg d−1
relevance, and that plasma concentrations following (though can be two or three times higher in
the consumption of such foods are theoretically vegetarians, found in vegetable oils, nuts, seeds,
sufficient to modulate the inflammatory response, a legumes and grains) and of plant stanols 10–50 mg d−1
mechanism which plays a key role in the pathogenesis (found in coconut and some vegetable oils). In
of chronic diseases.46,47 However, to date there have contrast, we eat 300–500 mg d−1 of cholesterol (in
been no human intervention studies to establish eggs and animal fats) and synthesize a further
whether salicylate-rich diets moderate markers of 800–1200 mg d−1 .48 Absorption of plant sterols is
inflammation in individuals at high risk of disease. low, as established in 1930 by Schönheimer, but
varies between types of plant sterol. While cholesterol
absorption is around 50%, absorption of sitostanol is
Lignans 1%, sitosterol 4%, campesterol 10% and campestanol
Lignans are also phenolic compounds that are present 13%.49,50
in many plant species. Although they are present in The first report of plant sterols reducing serum total
high concentrations in linseed (flax seed) they are cholesterol in humans was published in 1953.49 The
also present in measurable amounts in many of the plant sterol mixture used was ‘unpleasant to take’,
cereals, pulses, fruits and vegetables commonly con- with a ‘chalky appearance and taste, a dirty, off-white
sumed in the Western world. Although the levels of colour, and a gritty, sticky consistency’. Despite the
lignans are generally low on an individual food basis, difficulties of encouraging his patients to take this
their ubiquity in the plant kingdom suggests that they mixture for any length of time, Pollak showed that total
may well be an important source of phytoestrogens, cholesterol fell in 25 of his 26 participants over periods
particularly to consumers of high plant-based diets of 5–28 days. Some years later sitosterol was marketed
(e.g. vegans, vegetarians). The structure of lignans
in plants is rather different from the structure of the
mammalian lignans which are formed as a result of
microbial metabolism in the gut. The lignan precur-
sors (secoisolariciresinol, matairesinol) are present in
plants as glycoside conjugates, but following ingestion
microbial enzymes convert these precursors to entero-
diol and enterolactone. Confirmation for a bacterial
source for the production of the mammalian lignans
(enterodiol and enterolactone) was shown many years
ago when humans administered selective antibiotic
therapy over a 6- to 8-day period immediately showed
a decrease in enterodiol and enterolactone excretion
and after 2–3 days urinary excretion of the metabolites Figure 2. Comparison of the structures of cholesterol and the plant
was undetectable. In common with oestrogens and sterols and stanols.

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L Hooper, A Cassidy

as a lipid-lowering medication, but was removed from sterols to assess fully whether there is any difference
the market once statins became available.49,51 between them; however, there are suggestions that
Plant stanols and sterols appear to reduce serum over longer durations plant sterols might show reduced
LDL by reducing absorption of cholesterol from the effectiveness in lowering LDL cholesterol, while plant
intestinal tract. Cholesterol in the intestinal tract stanols continue to show maximal LDL reduction.48
is a combination of dietary cholesterol and biliary There are some potential problems associated with
cholesterol (released into the intestine to promote the use of high doses of plant stanols and sterols.
absorption of fats), the latter being by far the larger of Meta-analysis of randomized controlled trials suggests
the two sources at 500–2400 mg d−1 . It was thought significant reductions in serum concentrations of α-
that the reduction in absorption (or reabsorption) of tocopherol (reduction of 5.9%, 95% CI 3.8% to
cholesterol was due to cholesterol being displaced from 8.0%), α-carotene (reduction of 8.7%, 95% CI 3.5%
mixed micelles by plant stanols and sterols, increasing to 13.8%), β-carotene (−19.9%, 95% CI −15.0%
the amount of cholesterol excreted and depleting body to −24.9%) and lycopene (−7.3%, 95% CI −1.4%
stores. However, if this were the only mechanism, it to −13.1%), with no significant changes in retinol
would be expected that more frequent plant sterol (−0.1%, 95% CI −1.6% to +1.5%) or vitamin
ingestion (some with each meal) would improve the D (+0.5%, 95% CI −2.6% to +3.6%). These
reduction of cholesterol absorbed, and this has proven changes are probably not important in well-nourished
not to be the case. individuals but may cause problems over time for
A current hypothesis is that plant stanols and frail elderly people and children with marginal intakes
sterols move into enterocytes with cholesterol, but and/or absorption. In the UK we do not have set lower
that while cholesterol is rapidly esterified (by the reference nutrient intakes (LRNIs) for α-tocopherol,
enzyme acyl coenzyme A: cholesterol acyltransferase, α-carotene, β-carotene or lycopene, so it is difficult to
ACAT) plant stanol and sterols do not act as a specify what proportion of a population may have low
substrate for this enzyme.52,53 This leaves a raised intakes, but while the mean intake of β-carotene in
level of free stanol and/or sterol within the enterocytes people aged 65 and over was 1.5 mg d−1 , 23% of this
that act to increase the expression and/or activity of population were consuming less than 0.6 mg d−1 .54
cholesterol transport proteins back into the lumen. The incidence of sitosterolaemia (an inherited disorder
This increased transport of cholesterol, plant stanols where people preferentially accumulate sitosterol as
and sterols back into the intestinal lumen increases well as cholesterol, causing premature atherosclerosis)
the proportion of cholesterol that passes through the is extremely low (less than 1 per million population)
intestine unabsorbed, and decreases the amount of and is not a reason for concern over use of plant stanols
cholesterol esterified and passed into the circulation or sterols.
within chylomicrons. This induces a compensatory rise In summary, dietary intakes of plant sterols and
in cholesterol synthesis within the liver, but does not stanols (from vegetable oils, nuts, seeds, legumes and
fully restore serum LDL cholesterol. LDL receptor grains, eaten as part of a cardioprotective diet) may
expression is increased, hastening removal of LDL contribute to protection from cardiovascular disease
cholesterol from the circulation.53 through reduction of serum LDL, but the effects
A recent systematic review of the effects of plant are likely to be small (1–3% reductions in LDL
stanols and sterols suggests that the effect of at cholesterol) in people other than vegetarians. Use
least 1.5 g d−1 of plant stanols or sterols for periods of foods supplemented with plant sterols or stanols
of 10 days to 1 year in adults is a reduction in (neutraceuticals) can make a larger contribution of
LDL cholesterol of around 10%.48 There is a dose around 10% to LDL reduction, but care must be
response, with a maximal effect at 2.5 g d−1 (producing taken to ensure that the basic diet provides plentiful
a reduction of 11.3% LDL cholesterol, 95% CI fat-soluble vitamins.
10.2% to 12.3%), and an effect of about half this at
0.7–1.1 g of plant stanol or sterol per day (reduction Glucosinolates
of 6.7%, 95% CI 4.9% to 8.6% LDL cholesterol). Glucosinolates are a large group of sulfur-containing
The reduction in LDL cholesterol appears to be via compounds present in brassica vegetables which
a reduction in numbers of particles of LDL, rather are degraded into isothiocyanates by enzymatic
than through a reduction in their size or composition. action of plant-specific myrosinase or intestinal flora
LDL reductions appeared similar (around 10%) in in the body. Isothiocyanates (ITCs) have gained
diabetics and in people with varying apolipoprotein much attention because of their anticarcinogenic
E genotype. Use of plant stanols and sterols appears properties in culture models as well as in animal
to reduce LDL cholesterol by 10% over and above models. They are found in abundance in broccoli,
usual reductions seen through lipid-lowering diet or watercress, Brussels sprouts, cabbage and cauliflower,
use of statins. Little evidence is seen of change in and are responsible for their pungent odour and
levels of high-density lipoproteins or very-low-density flavour. Composition of the glucosinolates among
lipoproteins.52 cruciferous vegetables varies, depending on the
There have not yet been sufficient people involved in species, climate and other growing conditions. With
trials comparing the effects of plant stanols with plant physical stress such as chewing or chopping, the

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 Health care potential of bioactive compounds

plant cell wall ruptures and releases the plant- of toxicity to animals and occasionally to humans. For
specific enzyme myrosinase, which cleaves the glucose the majority of the currently identified phytochemicals
from the glucosinolate contained in raw vegetables. there is limited data on the ‘safe level’ of intake or
The remaining aglycone intermediate is unstable optimal level of intake for health benefits, and it is
and degrades into a number of biologically active critical that these margins are more clearly defined in
isothiocyanates, including phenethyl isothiocyanate future research.
(PEITC), sulforaphane and indole-3-carbinol. In
the human diet, cruciferous vegetables are usually
consumed after being cooked, and therefore the CONCLUDING REMARKS AND FUTURE
myrosinase is heat-inactivated. PROSPECTS
Exposure of cells to isothiocyanates has been Plants produce a wide variety of secondary metabo-
demonstrated to lead to rapid and high intracellular lites which may have health effects in humans. These
accumulation. Evidence of chemoprotective effects bioactives include flavones, flavonols, flavan-3-ols,
of isothiocyanates was first observed in rats several isoflavones, flavanones, anthocyanidins, lignans, sal-
decades ago, and a variety of experimental animal icylates, stanols, sterols and glucosinolates. There is
models have shown significant inhibitory effects evidence that these compounds are variably absorbed
on carcinogen-induced tumorigenesis.55 An inverse and metabolized in humans and appear biologically
relationship between high intake of cruciferous active in vitro. Potential mechanisms of action include:
vegetables and risk of cancer has been observed in
some case–control epidemiological studies,56 but the • reduced levels of circulating LDL;
available data are not consistent. These inconsistencies • enhanced antioxidant activity (potentially protecting
may relate to diet gene interactions. Lin et al.57 LDL from oxidation, so reducing their potential to
showed that the inverse relationship between the promote atherosclerotic plaque formation);
risks for colorectal adenoma and broccoli intake was • reduced platelet aggregation (reducing thrombotic
observed only in those with a genetic polymorphism potential);
of human glutathione S-transferase (GST) isozymes, • reduction in tumour development;
the GSTM1-null genotype. Zhao et al.58 reported that • ‘oestrogen-like’ activity, including effects on bone
higher weekly intake of isothiocyanates reduced the and breast health and menopausal symptoms;
risk of lung cancer to a greater extent among subjects • anti-inflammatory effects.
with homozygous deletion of GSTM1 and/or GSTT1.
London et al.59 found more significant association The activity of these compounds may partly explain
between urinary isothiocyanate level and reduced lung the strong correlations between fruit, vegetable, nut
cancer risks among men with homozygous deletion of and pulse intake, and reductions in diseases such as
GSTM1 or GSTT1 than with functional genotypes. cancers and cardiovascular diseases. Further research
The World Cancer Research Fund review of the role is needed to establish the health effects of specific
of diet in cancer prevention concluded that diets rich compounds, so that we can target intake of specific
in cruciferous vegetables probably protect humans compounds at people with specific health risks and
specifically against cancers of the colon, rectum, also develop foods with enhanced health profiles. This
thyroid and, when consumed as part of a diet rich is an exciting and vibrant area of investigation.
in other types of vegetables, against cancer at other
sites. The mechanism to explain these effects relate
to the ability of glucosinolate breakdown products REFERENCES
(e.g. the isothiocyanates, sulfuraphane) to modulate 1 Hu FB and Willett WC, Optimal diets for prevention of
coronary heart disease. JAMA 288:2569–2578 (2002).
the activities of Phase I (e.g. cytochrome P450s) 2 Jenkins DJ, Kendall CW, Marchie A, Faulkner DA, Josse AR,
and Phase II (e.g. glutathione S-transferase, UDP- Wong JM, et al. Direct comparison of dietary portfolio vs
glucuronyl transferase) biotransformation enzymes statin on C-reactive protein. Eur J Clin Nutr 59:851–860
which together catalyse a variety of hydrolytic, (2005).
oxidation or reduction reactions (Phase I), the 3 Hu FB, The role of diet and lifestyle modifications in the statin
era. J Am Diet Assoc 105:1718–1721 (2005).
products of which are then available for conjugation 4 Collins R, Armitage J, Parish S, Sleigh P and Peto R,
reactions (Phase II). MRC/BHF Heart Protection Study of cholesterol-lowering
with simvastatin in 5963 people with diabetes: a randomised
placebo-controlled trial. Lancet 361:2005–2016 (2003).
5 Hollman PC, van Trijp JM, Buysman MN, van der Gaag MS,
SAFETY Mengelers MJ, de Vries JH, et al, Relative bioavailability of
The concept that phytochemicals are potentially the antioxidant flavonoid quercetin from various foods in
beneficial to human health is rapidly gaining both man. FEBS Lett 418:152–156 (1997).
scientific and public credence. Although in the future 6 Setchell KD, Brown NM, Desai P, Zimmer-Nechemias L,
Wolfe BE, Brashear WT, et al, Bioavailability of pure
sufficient convincing evidence may well be available to
isoflavones in healthy humans and analysis of commercial soy
prove potential health benefits from consumption of isoflavone supplements. J Nutr 131:1362S–1375S (2001).
some of the phytochemicals addressed in this chapter, 7 Faughnan MS, Hawdon A, Ah-Singh E, Brown J, Millward DJ
for several other phytochemicals there is clear evidence and Cassidy A, Urinary isoflavone kinetics: the effect of age,

J Sci Food Agric 86:1805–1813 (2006) 1811

DOI: 10.1002/jsfa
L Hooper, A Cassidy

gender, food matrix and chemical composition. Br J Nutr 26 Nestel PJ, Pomeroy S, Kay S, Komesaroff P, Behrsing J,
91:567–574 (2004). Cameron JD, et al, Isoflavones from red clover improve sys-
8 Scalbert A and Williamson G, Dietary intake and bioavailability temic arterial compliance but not plasma lipids in menopausal
of polyphenols. J Nutr 130:2073S–2085S (2000). women. [Erratum in: J Clin Endocrinol Metab 84(10):3647
9 Donovan JL, Bell JR, Kasim-Karakas S, German JB, Walzem (1999)]. J Clin Endocrinol Metab 84:895–898 (1999).
RL, Hansen RJ, et al, Catechin is present as metabolites 27 Cassidy A, Bingham S and Setchell K, Biological effects of
in human plasma after consumption of red wine. J Nutr isoflavones in young women: importance of the chemical
129:1662–1668 (1999). composition of soyabean products. Br J Nutr 74:587–601
10 Williamson G and Manach C, Bioavailability and bioefficacy of (1995).
polyphenols in humans. II. Review of 93 intervention studies. 28 Davis JN, Kucuk O, Djuric Z and Sarkar FH, Soy isoflavone
Am J Clin Nutr 81:243S–255S (2005). supplementation in healthy men prevents NF kappa B
11 Sano A, Yamakoshi J, Tokutake S, Tobe K, Kobuta Y and activation by TNF-alpha in blood lymphocytes. Free Radic
Kikuchi M, Procyanidin B1 is detected in human serum after Biol Med 30:1293–1302 (2001).
intake of proanthocyanidin-rich grape seed extract. Biosci 29 Djuric Z, Chen G, Doerge DR, Heilbrun LK and Kucuk O,
Biotechnol Biochem 67:1140–1143 (2003). Effect of soy isoflavone supplementation on markers of
12 Holt RR, Lazarus SA, Sullards MC, Zhu QY, Schramm DD, oxidative stress in men and women. Cancer Lett 172:1–6
Hammerstone JF, et al, Procyanidin dimer B2 [epicatechin- (2001).
(4beta-8)-epicatechin] in human plasma after the consump- 30 Coward L, Barnes NC, Setchell KDR and Barnes S, Genistein,
tion of a flavanol-rich cocoa. Am J Clin Nutr 76:798–804 daidzein, and their beta-glycoside conjugates – antitumor
(2002). isoflavones in soybean foods from American and Asian diets.
13 Manach C, Williamson G, Morand C, Scalbert A and Journal of Agricultural and Food Chemistry 41:1961–1967
Remesy C, Bioavailability and bioefficacy of polyphenols in (1993).
humans. I. Review of 97 bioavailability studies. Am J Clin 31 Setchell KD and Cole SJ, Variations in isoflavone levels in soy
Nutr 81:230S–242S (2005). foods and soy protein isolates and issues related to isoflavone
14 Manach C, Morand C, Gil-Izquierdo A, Bouteloup-Demange databases and food labeling. J Agric Food Chem 51:4146–4155
C and Remesy C, Bioavailability in humans of the flavanones (2003).
hesperidin and narirutin after the ingestion of two doses of 32 Axelson M, Sjovall J, Gustafsson BE and Setchell KD, Soya: a
orange juice. Eur J Clin Nutr 57:235–242 (2003). dietary source of the non-steroidal estrogen equol in man and
15 Erlund I, Meririnne E, Alfthan G and Aro A, Plasma kinetics animals. J Endocrinol 102:49–56 (1984).
33 Setchell KDR, Borriello SP, Hulme P, Kirk DN and Axel-
and urinary excretion of the flavanones naringenin and
son M, Nonsteroidal estrogens of dietary origin: possible roles
hesperetin in humans after ingestion of orange juice and
in hormone-dependent disease. Am J Clin Nutr 40:569–578
grapefruit juice. J Nutr 131:235–241 (2001).
(1984).
16 Kurowska EM and Manthey JA, Hypolipidemic effects and
34 Nagata C, Takatsuka N, Kurisu Y and Shimizu H, Decreased
absorption of citrus polymethoxylated flavones in hamsters
serum total cholesterol concentration is associated with high
with diet-induced hypercholesterolemia. J Agric Food Chem
intake of soy products in Japanese men and women. J Nutr
52:2879–2886 (2004).
128:209–213 (1998).
17 Franke AA, Custer LJ, Cooney RV, Tanaka Y, Xu M and
35 Munro IC, Harwood M, Hlywka JJ, Stephen AM, Doull J,
Dashwood RH, Inhibition of colonic aberrant crypt formation
Flamm WG and Adlercreutz H, Soy isoflavones: a safety
by the dietary flavonoids (+)-catechin and hesperidin. Adv
review. Nutr Rev 61(1):1–33 (2003).
Exp Med Biol 505:123–133 (2002).
36 Erdman JW Jr, Badger TM, Lampe JW, Setchell KD and
18 Setchell KDR and Cassidy A, Dietary isoflavones: biological
Messina M, Not all soy products are created equal: cau-
effects and relevance to human health. J Nutr 129:758S–767S
tion needed in interpretation of research results. J Nutr
(1999). 134(5):1229S–1233S (2004).
19 Cassidy A, Albertazzi P, Lise Nielsen I, Hall W, Williamson G, 37 Seow A, Shi CY, Franke AA, Hankin JH, Lee HP and Yu MC,
Tetens I, Atkins S, Cross H, Manios Y, Wolk A, Steiner C Isoflavonoid levels in spot urine are associated with frequency
and Branca F, Critical review of health effects of soyabean of dietary soy intake in a population-based sample of middle-
phyto-oestrogens in post-menopausal women. Proc Nutr Soc aged and older Chinese in Singapore. Cancer Epidemiol
65(1):76–92 (2006). Biomarkers Prev 7:135–140 (1998).
20 Phipps WR, Duncan AM and Kurzer MS, Isoflavones and 38 Wakai K, Egami I, Kato K, Kawamura T, Tamakoshi A, Lin Y,
postmenopausal women: a critical review. Treat Endocrinol et al, Dietary intake and sources of isoflavones among
1(5):293–311 (2002). Japanese. Nutr Cancer 33:139–145 (1999).
21 Adlercreutz H, Fotsis T, Bannwart C, Wahala K, Makela T, 39 Chen Z, Zheng W, Custer LJ, Dai Q, Shu XO, Jin F, et al,
Brunow G, et al, Determination of urinary lignans and phy- Usual dietary consumption of soy foods and its correlation
toestrogen metabolites, potential antiestrogens and anticar- with the excretion rate of isoflavonoids in overnight urine
cinogens, in urine of women on various habitual diets. J samples among Chinese women in Shanghai. Nutr Cancer
Steroid Biochem 25:791–797 (1986). 33:82–88 (1999).
22 Beral V, Million Women Study Collaborators. Breast cancer 40 Setchell KDR, Faughnan MS, Avades T, Zimmer-
and hormone-replacement therapy in the Million Women Nechemias L, Brown NM, Wolfe BE, et al, Comparing the
Study. Lancet 362(9382):419–27 (2003); Erratum in: Lancet pharmacokinetics of daidzein and genistein with the use of
362(9390):1160 (2003). 13C-labeled tracers in premenopausal women. Am J Clin Nutr
23 Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooper- 77:411–419 (2003).
berg C, Stefanick ML, et al, Risks and benefits of estrogen 41 Faughnan MS, Hawdon A, Ah-Singh E, Brown J, Millward DJ
plus progestin in healthy postmenopausal women: princi- and Cassidy A, Urinary isoflavone kinetics: the effect of age,
pal results from the Women’s Health Initiative randomized gender, food matrix and chemical composition. Br J Nutr
controlled trial. JAMA 288:321–333 (2002). 91:567–574 (2004).
24 McPherson K, Where are we now with hormone replacement 42 Signorelli P and Ghidoni R, Resveratrol as an anticancer
therapy? It works for symptoms but is not good for future nutrient: molecular basis, open questions and promises. J
health. Br Med J 328:357–358 (2004). Nutr Biochem 16:449–466 (2005).
25 Cassidy A, Bingham S and Setchell KD, Biological effects of a 43 Frankel EN, Kanner J, German JB, Parks E and Kinsella JE,
diet of soy protein rich in isoflavones on the menstrual cycle of Inhibition of oxidation of human low-density lipoprotein by
premenopausal women. Am J Clin Nutr 60:333–340 (1994). phenolic substances in red wine. Lancet 341:454–457.

1812 J Sci Food Agric 86:1805–1813 (2006)

DOI: 10.1002/jsfa
 Health care potential of bioactive compounds

44 Pendurthi UR and Rao LV, Resveratrol suppresses agonist- in the management of blood cholesterol levels. Mayo Clin Proc
induced monocyte adhesion to cultured human endothelial 78:965–978 (2003).
cells. Thromb Res 106:243–248 (2002). 53 Plat J and Mensink RP, Plant stanol and sterol esters in the
45 Paterson JR, Blacklock C, Campbell G, Wiles D, and control of blood cholesterol levels: mechanism and safety
Lawrence JR, The identification of salicylates as normal aspects. Am J Cardiol 96(suppl 1):15–22 (2005).
constituents of serum: a link between diet and health? J 54 Finch S, Doyle W, Lowe C, Bates CJ, Prentice A, Smithers G
Clin Pathol 51:502–505 (1998). and Clarke PC, National Diet and Nutrition Survey: People
46 Lawrence JR, Peter R, Baxter GJ, Robson J, Graham AB and Aged 65 years and over. Vol. 1: Report of the Diet and Nutrition
Paterson JR, Urinary excretion of salicyluric and salicylic acids Survey, TSO, London, (1998).
by non-vegetarians, vegetarians, and patients taking low dose 55 Keum YS, Jeong WS and Kong AN, Chemoprevention by
aspirin. J Clin Pathol 56:651–653 (2003). isothiocyanates and their underlying molecular signaling
47 Duthie GG, Kyle JA, Jenkinson AM, Duthie SJ, Baxter GJ and mechanisms. Mutat Res 555:191–202 (2004).
Paterson JR, Increased salicylate concentrations in urine of 56 Kristal AR and Lampe JW, Brassica vegetables and prostate
human volunteers after consumption of cranberry juice. J cancer risk: a review of the epidemiological evidence. Nutr
Agric Food Chem 53:2897–2900 (2005). Cancer 42:1–9 (2002).
48 Clifton P, Plant sterol and stanols: comparison and contrasts. 57 Lin HJ, Probst-Hensch NM, Louie AD, Kau IH, Witte JS,
Sterols versus stanols in cholesterol-lowering: is there a Ingles SA, et al, Glutathione transferase null genotype,
difference? Atheroscler Suppl 3:5–9 (2002). broccoli, and lower prevalence of colorectal adenomas. Cancer
49 Czubayko F, Beumers B, Lammsfuss S, Lutjohann D and von Epidemiol Biomarkers Prev 7:647–652 (1998).
Bergmann K, A simplified micro-method for quantification 58 Zhao B, Seow A, Lee EJ, Poh WT, Teh M, Eng P, et al,
of fecal excretion of neutral and acidic sterols for outpatient Dietary isothiocyanates, glutathione S-transferase -M1, -T1
studies in humans. J Lipid Res 32:1861–1867 (1991). polymorphisms and lung cancer risk among Chinese women
50 Heinemann T, Axtmann G and von Bergmann K, Comparison in Singapore. Cancer Epidemiol Biomarkers Prev 10:1063–1067
of intestinal absorption of cholesterol with different plant (2001).
sterols in man. Eur J Clin Invest 23:827–831 (1993). 59 London SJ, Yuan JM, Chung FL, Gao YT, Coetzee GA,
51 Pollak OJ, Reduction of blood cholesterol in man. Circulation Ross RK, et al, Isothiocyanates, glutathione S-transferase M1
7:702–706 (1953). and T1 polymorphisms, and lung-cancer risk: a prospec-
52 Katan MB, Grundy SM, Jones P, Law M, Miettinen T and tive study of men in Shanghai, China. Lancet 356:724–729
Paoletti R, Efficacy and safety of plant stanols and sterols (2000).

J Sci Food Agric 86:1805–1813 (2006) 1813

DOI: 10.1002/jsfa