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Potential Impact of Strawberries on Human Health: AReview of the ScienceSANDRA M. HANNUM aa Nutritional Sciences, University of IllinoisPublished online: 10 Aug 2010.

To cite this article: SANDRA M. HANNUM (2004) Potential Impact of Strawberries on Human Health: A Review of the Science,Critical Reviews in Food Science and Nutrition, 44:1, 1-17, DOI: 10.1080/10408690490263756

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Critical Reviews in Food Science and Nutrition, 44:1–17 (2004)Copyright C©© Taylor and Francis Inc.ISSN: 1040-8398DOI: 10.1080/10408690490263756

Potential Impact of Strawberrieson Human Health: A Reviewof the Science

SANDRA M. HANNUM, MS, RDNutritional Sciences, University of Illinois

Epidemiological studies have noted a consistent association between the consumption of diets rich in fruits and vegetablesand a lower risk for chronic diseases including cancer and cardiovascular disease. There is accumulating evidence that muchof the health-promoting potential of these plant foods may come from phytochemicals, bioactive compounds not designatedas traditional nutrients. In strawberries, the most abundant of these are ellagic acid, and certain flavonoids: anthocyanin,catechin, quercetin and kaempferol.

These compounds in strawberries have potent antioxidant power. Antioxidants help lower risk of cardiovascular events byinhibition of LDL-cholesterol oxidation, promotion of plaque stability, improved vascular endothelial function, and decreasedtendency for thrombosis. Furthermore, strawberry extracts have been shown to inhibit COX enzymes in vitro, which wouldmodulate the inflammatory process. Individual compounds in strawberries have demonstrated anticancer activity in severaldifferent experimental systems, blocking initiation of carcinogenesis, and suppressing progression and proliferation of tumors.Preliminary animal studies have indicated that diets rich in strawberries may also have the potential to provide benefits tothe aging brain.

Keywords berries, phytochemicals, ellagic acid, flavonoid, anthocyanin, catechin, quercetin, kaempferol

BACKGROUND

The link between diet and health has been recognized sinceancient times. The earliest physicians treated their patients withherbs and foods believed to have medicinal properties.1 Al-though modern physicians have depended more on synthesizedmedicines, there is a growing appreciation for the significantrole that food plays in health.

Epidemiological studies have noted a consistent associationbetween the consumption of diets rich in fruits and vegetablesand a lower risk for chronic diseases, including cancer,1–3 heartdisease,4,5 and stroke.6,7 Additional benefits that are likely tofollow from increased consumption of these plant foods includebetter diabetes control and reduced risk of obesity, because of thehigh fiber and low calorie content of such a diet.1 Although fruitsand vegetables account for only about 5 to 10% of total caloriesconsumed, they make a significant contribution to overall health.

Based on the strength of the association between fruit andvegetable consumption and health, various organizations haverecommended that the entire US population increase its con-sumption of these foods. In 1982 the National Academy of Sci-ences produced a report on diet and cancer, which included a di-

etary guideline emphasizing the importance of consuming fruitsand vegetables.8 The benefits of citrus fruits, carotene-rich fruitsand vegetables, and cruciferous vegetables for reducing cancerrisk were emphasized. In 1989 the National Academy producedanother report entitled Diet and Health, which recommended anintake of at least 5 servings per day of fruits and vegetables inorder to reduce risk of both cancer and heart disease.9 In 1991,the 5 A Day For Better Health program was launched by theNational Cancer Institute.10 Since 1977 all of the dietary guide-lines issued by health agencies have recommended an increasein consumption of fruits and vegetables for all Americans.11

Scientists have begun to single out groups of fruits and veg-etables that are associated with specific health benefits. For ex-ample, cruciferous vegetables, allium vegetables and tomatoesare associated with lower risk for certain cancers,1 while tea,onions and apples are associated with lower risk for coronaryheart disease.4 This intriguing area of research is just beginningto emerge. Given the tremendous variety of fruits and vegetablesavailable for consumption, there is much more work to be donebefore the potential benefits of all these foods are understood.

Fruits and vegetables tend to be rich in vitamins, minerals andfiber. In addition, these foods contain other potentially bioactive

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2 S. M. HANNUM

compounds, or phytochemicals, which are not designated as tra-ditional nutrients. Research with these plant compounds hasdemonstrated that they take many forms and produce a vari-ety of biological effects. Clearly, not all fruits and vegetablesare the same. To obtain the maximum health benefit from diet,nutrition experts recommend consuming a wide variety of thesefoods.12 Different classes of plant foods contain different com-binations of phytochemicals. In the specific foods mentionedabove, it is the phytochemicals that appear to provide much ofthe disease-fighting power.

PHYTOCHEMICALS

The phytochemicals that have been studied most extensivelyare the phenolic compounds. Phenolic compounds are productsof plant metabolism that likely serve many functions essentialto the growth and survival of the plant. It is now clear that thesecompounds are also bioactive in animals and humans who con-sume them.

Phenolic compounds are composed of one or more aromaticrings bearing one or more hydroxyl groups. They are found infoods in a range of sizes, from simple molecules to very largeoligomers. Frequently, the phenolic compounds in foods occuras glycosides. The attached sugars make these compounds morewater-soluble.13–15 However, the very high-molecular-weightoligomers are usually insoluble.

There are hundreds of different phenolic compounds in plantfoods, but about two thirds of those most commonly consumedare flavonoids and about one third are phenolic acids.15

Flavonoids are known to be potent antioxidants. Their abilityto scavenge hydroxyl and peroxyl radicals has been demon-strated repeatedly in vitro.16,17 Phenolic acids may also be fairlygood antioxidants, depending on their structures.18,19 Bothflavonoids and phenolic acids may work synergistically withother antioxidants, such as ascorbate and tocopherol, and seemto have a sparing effect on these vitamins.14 Another way inwhich flavonoids exert an antioxidant effect is by chelating met-als, and thus inhibiting production of free radicals.

The antioxidant activity of these dietary phenolic compoundssuggests that they may reduce oxidative stress in humans andthus may lower risk for several chronic diseases.20 Epidemio-logical work has shown a positive association between flavonoidconsumption and reduced risk of coronary heart disease,4,21 al-though not all studies have supported this.22 One weakness ofthese studies is the lack of information on actual flavonoid con-tent of foods. The USDA has recently compiled a database onflavonoid content of selected foods, which is available on theirwebsite.23

There are several subclasses of flavonoids in foods. In straw-berries, the most abundant of these are the anthocyanins, thecatechins, and the flavonols quercetin and kaempferol. In addi-tion, strawberries are extremely rich in the phenolic acid, ellagicacid. There is a large body of literature on the biological effectsof the above-mentioned compounds in strawberries, although

there is little on the health effects of strawberry consumptionper se. This review focuses on current understanding of the phy-tochemicals found in strawberries and their potential bioactivity.

PHENOLIC COMPOUNDS IN STRAWBERRIES

Table 1 shows some of the values that have been reported forcontent of certain phenolic compounds in strawberries. Clearlythere is tremendous variation in the reported data. Phenolic con-tent of strawberries varies with the cultivar, growing conditions,degree of ripeness, and handling after harvest. Variability in thedata is also due to methodological differences, since there is alack of agreement on what is the appropriate method to ana-lyze these compounds.13 All of these factors make it difficult tocompare the results of different research studies.

Ellagic Acid

Ellagic acid is a phenolic acid which occurs in strawber-ries, both in the free form and esterified to glucose in water-soluble hydrolyzable ellagitannins. Hakkinen et al. estimate thatellagic acid comprises 51% of the phenolic compounds instrawberries.24

In their review, Tomas-Barberan and Clifford pointed out thatalthough all the common analytical techniques for measuringellagic acid have good accuracy and reproducibility, the resultsdiffer depending on the method of extraction used and whetherthe extract is hydrolyzed before analysis.25 Since ellagic acid isfairly insoluble in water, it is easy to underestimate the contentif an aqueous solvent is used for extraction. Furthermore, ifthe extract is hydrolyzed before being analyzed, the ellagic acidcontent evaluation is more accurate because it includes both freeand conjugated forms of this phenolic acid.

Daniel et al. found that strawberries contained 63 µg of el-lagic acid/g fresh weight.26 This was lower than the contentfound in raspberries and blackberries, but much higher thanthat of the other 18 fruits tested. Table 2 shows the results ofthese analyses. All fruits in this study were analyzed by thesame method, which included a 2-hour hydrolysis. An impor-tant point made by these researchers is that in raspberries, 87.8%of the ellagic acid was found in the seeds, whereas in strawber-ries, 95.7% of the ellagic acid was found in the pulp. For thisreason, it is likely that the ellagic acid in strawberries is morebioavailable. Furthermore, these three types of berries containabout three times as much ellagic acid as walnuts and pecans,and at least fifteen times as much as other fruits and nuts.26

Gil et al. reported only 19.9 µg ellagic acid/g in their straw-berry samples, which were analyzed without hydrolysis.27

Hakkinen et al. found 403 µg/g in strawberry samples that werehydrolyzed for 20 hours.24

Hakkinen has done extensive research into the factors thataffect phenolic content in berries, including analysis of differ-ent cultivars, and analysis following various storage methods.

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Tabl

e1

Phen

olic

cont

ento

fst

raw

berr

ies

(fre

shw

eigh

t)

Tota

lphe

nolic

sQ

uerc

etin

Kae

mpf

erol

Cat

echi

nsA

ntho

cyan

inE

llagi

cac

id

Dan

iele

tal.,

1989

2663

µg/

g1

Wan

get

al.,

1990

161

155

µg/

gH

erto

get

al.,

1992

162

8.6

µg/

g12

.0µ

g/g

Gil

etal

.,19

9727

40.1

µg/

g13

.7µ

g/g

120.

2µ

g/g

19.9

µg/

gH

eino

nen

etal

.,19

9840

2940

µg

GA

E/g

2

70%

acex

trac

tion

786

µg/

g70

%ac

extr

actio

nK

alte

tal.,

1999

3286

4.2

µg

GA

E/g

2,3

(5.0

8µ

mol

GA

E/g

)51

.24

µg

Mal

-3-g

lu/g

4

(0.1

55µ

mol

Mal

-3-g

lu/g

)A

rts

etal

.,20

0033

44.7

µg/

gde

Pasc

ual-

Tere

saet

al.,

2000

3449

.1µ

g/g

(all

form

s)H

akki

nen

etal

.,20

00a24

403

µg/

gH

akki

nen

and

Tor

rone

n,20

00b28

421–

544

µg/

g(n

otin

clud

ing

anth

ocya

nins

)3–

5µ

g/g

2–9

µg/

g39

6–52

2µ

g/g

Wan

gan

dL

in,2

000b

3196

0µ

g/g

389

µg/

gN

yman

and

Kum

pula

inen

,200

12937

8µ

g/g

1C

onve

rted

from

dry

wei

ghtb

ased

onas

sum

ptio

nof

90%

wat

erin

fres

h.2G

AE

=ga

llic

acid

equi

vale

nts.

3C

onve

rted

from

µm

olva

lue

base

don

170.

12m

olec

ular

wei

ghto

fga

llic

acid

.4C

onve

rted

from

µm

olva

lue

base

don

330.

61m

olec

ular

wei

ghto

fm

alvi

din.

3

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Table 2 Ellagic acid content of foods

Food µg/g dry weight

Strawberries Fragaria ananassa 630Raspberries 1500Blackberries 1500Cranberries 120Pecans 330Walnuts 590Brazil nuts, peanuts, cashews, apples (red), oranges

(navel), grapefruit (pink & white), tangerine, tangelo,peach (brown and green), pear (brown), grape (white& red), cherry (sour and bing), elderberry, plum (blue,blueberries, kiwi

<100

Daniel et al., 1989.26

Ellagic acid content in different strawberry cultivars varied from396 µg/g in Senga Sengana to 522 µg/g in Jonsok.28 Maas et al.reported even larger differences among cultivars, with ellagicacid content ranging from 43 to 464 µg/g fresh weight.29

Metabolism is known to continue in fruits after they are har-vested. Post-harvest storage temperature (5◦ or 22◦C) had nosignificant effect on ellagic acid content in the first 24 hours.24

However, Gil found that free ellagic acid content increased overthe course of 10 days post-harvest at 5◦C, probably becauseellagitannins were degraded. The increase in ellagic acid oc-curred more slowly when the fruits were stored in a high CO2

atmosphere.27 Frozen strawberries stored for 9 months at −20◦Chad a 40% decrease in ellagic acid content.24 Ellagic acid con-tent of hydrolyzed strawberry jam was about 80% of that in freshberries, then remained stable in storage. In unhydrolyzed sam-ples, the content of free ellagic acid was increased by 150% instrawberries during processing into jam.25

Anthocyanin Content

Anthocyanins comprise a large subclass of flavonoid plantpigments that provide most of the red, blue and purple colors offlowers and fruits. The structure of anthocyanins is pH depen-dent, having a red color at pH below 2, and changing to blueand finally colorless as the pH increases.30 In strawberries, theanthocyanins are the most abundant flavonoids.

All naturally occurring anthocyanins are glycosides, withthe corresponding aglycones being called anthocyanidins. Re-searchers who are measuring anthocyanin content of foods haveto decide whether to measure the intact anthocyanins or theaglycone forms. Because anthocyanins are unstable compounds,standards for all the various forms are expensive and hard tomaintain.30

Table 1 lists the anthocyanin content of strawberries as re-ported by several researchers. Again, there is a great deal of vari-ation in the data. Anthocyanin content increases with ripenessof the fruit, changing from 2 µg/g in small green strawberriesto 389 µg/g in fully ripe berries.31 Kalt demonstrated that theanthocyanin content of strawberries increased during 8 daysof storage. The magnitude of the change was temperature-

dependent, increasing 1.7-fold at 0◦C and 6.8-fold at 30◦C.32

Gil found that storage in a CO2 enriched atmosphere decreasedthe anthocyanin content of strawberries, particularly in internaltissue.27

Flavanol and Flavonol Content

Catechin is a monomeric flavanol compound. This compoundis difficult to measure because it is usually present in foods as partof a complex mixture of phenolic substances. Because of this,the amount of catechin present is sometimes overestimated.33

The various forms of the catechins have been studied mostly intea, although high quantities are also found in certain chocolates,apples, red grapes, and berries.

Quercetin and kaempferol belong to the subclass of flavonoidscalled flavonols. Quercetin in particular has been studied morethan any other flavonoid, and a great deal is known about itsbioactivity. Flavonols represent approximately 11% of the phe-nolic compounds present in strawberries.28

Table 1 shows some of the reported data on the catechin,quercetin and kaempferol content of strawberries. Two papershave reported moderate levels of catechin.33,34 Among the fruitsthat have been analyzed, kaempferol is found in only strawber-ries and gooseberries.35

Like the other phenolic compounds, flavanols and flavonolsare affected by processing and storage. Studies of catechin con-tent in grape juice found that heat treatments, such as pasteuriza-tion, cause both polymerization of monomers and depolymeriza-tion of oligomers, resulting in very little net change in catechincontent.36 Studies of tea catechins also showed that extensiveisomerization occurs with heat treatments, involving conversionof catechin to epicatechin and vice-versa.37 However, when heattreatment is excessive, it leads to further degradation, and a lossof total catechin concentration.36,37

Catechin is unstable in alkaline conditions. Although it usu-ally degrades rapidly at a pH >6, an in vitro study showed thatascorbic acid protected catechin from degradation even at a neu-tral pH, although citric acid did not.38 Since strawberries are veryhigh in ascorbic acid content, it would be reasonable to speculatethat the catechin in this fruit may be somewhat protected.

Gil et al. found that concentrations of both quercetin andkaempferol increased during 10 days of storage in a CO2-enriched environment.27 In frozen strawberries, kaempferol ismore vulnerable to losses than quercetin. In fact, Hakkinen foundthat after 9 months of storage at −20◦C, quercetin content in-creased by 32%, while kaempferol was no longer detectable.Cooking strawberries to make jam caused losses of 18% of thequercetin and 15% of the kaempferol. In contrast, the loss of vita-min C was 36%.24 Flavonol losses were minimized by not crush-ing the fruit before cooking. Also, the flavonols were spared fromenzymatic action since the heat inactivates the polyphenol oxi-dase. When juices are made from berries by common methods,the majority of the flavonols are lost. Quercetin is particularlysusceptible to loss during crushing.24

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POTENTIAL IMPACT OF STRAWBERRIES ON HUMAN HEALTH 5

Hakkinen and Torronen studied the quercetin and kaempferolcontent of six different Finnish strawberry cultivars and foundthe variations to be fairly small. Quercetin content ranged from3 µg/g in Senga Sengana to 5 µg/g in Honeoye. Kaempferolcontent ranged from 2 µg/g in Jonsok to 9 µg/g in Honeoye.Interestingly, in a comparison of organically grown to conven-tionally grown strawberries, kaempferol levels were higher inthe organic fruits. The researchers speculated that perhaps theorganic plant had increased production of this flavonol in re-sponse to an attack by a pathogen, since kaempferol is one ofthe antimicrobial compounds produced by the plants.28

ANTIOXIDANT CAPACITY OF PHENOLICCOMPOUNDS

The fact that phenolic compounds have antioxidant activityhas been demonstrated repeatedly in vitro.16,17,31,32,39–41

Flavonoids in particular are potent antioxidants, partly becausethey are effective scavengers of hydroxyl and peroxyl radicals. Inan in vitro model of heart disease in which low density lipopro-tein (LDL) oxidation was measured, Vinson et al. found thatmany flavonoids were considerably more powerful antioxidantsthan vitamins C and E.42 Phenolic acids also may be fairly goodantioxidants, depending on their structures.18,19 Both flavonoidsand phenolic acids may work synergistically with other antiox-idants such as ascorbate and tocopherol and seem to have asparing effect on these vitamins.14

Guo et al. quantified phenolic acid and flavonoid antioxidantsin fruits and vegetables by using a reversed-phase chromatogra-phy system with ultraviolet and visible absorbance detection.39

This procedure produces a “fingerprint” of all the antioxidantsin foods. Table 3 shows the number of peaks and the total peakarea for each food. Among the 24 fruits and vegetables tested,strawberries had the second highest number of peaks and thefifth highest total peak area, indicating that strawberries were

Table 3 Number of antioxidants and total antioxidant activityof selected fruits and vegetables

Item No. of peaks Peak area ORAC

FruitStrawberry 75 379.6 2.68Orange 65 429.2 1.94Red grape 31 92.5 1.24Kiwifruit 20 201.1 1.08Apple 20 17.6 0.49Banana 15 40.9 0.46Pear 12 27.5 0.46Honeydew melon 7 24.3 0.20

VegetableKale 117 317.5 2.70Brussels sprouts 74 225.3 1.73Green pepper 20 400.4 1.79Eggplant 8 70.9 0.90Cabbage 33 73.7 0.49Tomato 15 100.0 0.45

Guo et al., 1997.39

Table 4 Mean values of antioxidant activity, anthocyanin content andtotal phenolic content in fruit juice of different berries (dry weight)

ORAC1 Anthocyanin Total phenolicsSpecies (µmol of TE/g) (mg/100 g) (mg GAE/100 g)

Blackberry 133.3 909.3 1347Black raspberry 136.2 952.1 1535Red raspberry 104.3 391.8 1346Strawberry2,3 147.7 315.2 1033

1TE = Trolox equivalents. The ORAC activity of 1 mol of α-tocopherolequals one mol of TE, the ORAC activity of 1 µmol of vitamin C equals0.52 µmol of TE.

2Data expressed as mg of pelargonidin-3-glucoside.3Mean of eight cultivars, Allstar, Delmarvel, Earliglow, Latestar, Lester,

Mohawk, Northeaster, and Red Chief.Adapted from Wang and Lin, 2000b.31

rich in phenolic compounds. In addition to the phenolics, straw-berries contained 583 µg vitamin C/g fresh weight and 83 µgglutathione/g, which are also antioxidants. By using the oxygenradical absorbance capacity (ORAC) assay, the researchersdemonstrated a significant positive correlation between the phe-nolic content of the foods and their antioxidant capacity. Guo’slaboratory determined that strawberry had 1.3 times the antiox-idant activity of oranges, twice that of red grapes, five timesthat of apples and bananas, and thirteen times that of honeydewmelon.39

In 1996 Wang et al. determined the antioxidant activity of12 fruits and found that strawberries had the highest total an-tioxidant activity. These researchers used an artificial peroxylradical system to measure antioxidant activity compared to atrolox (vitamin E analog) standard. Vitamin C content was notdirectly related to total antioxidant activity; therefore the re-searchers concluded that the activity was likely due to the phe-nolic compounds.43 In a later study focusing on berries, Wangand Lin found a clear linear relationship between ORAC val-ues and total phenolic content for blackberry, raspberry, andstrawberry.31 Table 4 shows the results for different types ofberries. Interestingly, this study also investigated the effects ofvariety (Table 5) and maturity (Table 6) on antioxidant capacity.

Table 5 Antioxidant activity, anthocyanin content, and totalphenolic content of juices from various cultivars of ripe strawberryfruits (dry weight)

ORAC1 Anthocyanin2 Total phenolicsCultivars (µmol of TE/g) (mg/100 g) (mg GAE/100 g)

Allstar 120.8 230.7 943Delmarvel 130.7 266.3 1180Earliglow 172.3 448.5 1507Latestar 132.7 244.6 1061Lester 157.4 353.3 1239Mohawk 160.4 311.9 1358Northeaster 166.3 382.2 1388Red chief 140.6 284.2 1195

1TE = Trolox equivalents.2Data expressed as mg of pelargonidin-3-glucoside.Adapted from Wang and Lin, 2000b.31

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Table 6 Antioxidant activity, anthocyanin content, and totalphenolic content of juices from of strawberry (cv. allstar) fruits atdifferent stages of maturity (dry weight)

ORAC1 Anthocyanin2 Total phenolicsMaturity (µmol of TE/g) (mg/100 g) (mg GAE/100 g)

Small green 160.9 1.4 1971Large green 144.2 2.9 1696White 96.8 26.2 1394Pink 82.4 46.2 108350% red 81.8 143.4 91680% red 95.4 216.5 971Full red 118.8 385.1 946

1TE = Trolox equivalents.2Data expressed as mg of pelargonidin-3-glucoside.Adapted from Wang and Lin, 2000b.31

For ripe berries, there is a linear relationship between ORACvalues and anthocyanin content. As noted in Table 6, antho-cyanin increases with maturity, but the content of certain otherphenolics decreases.

A study by Kalt demonstrated a strong correlation betweenORAC values and content of total phenolics, as well as withanthocyanins.32 This study included blueberries, which werefound to have an antioxidant capacity 3-fold higher than that ofstrawberries and raspberries. However, the antioxidant activityfor strawberries reported by Kalt was actually 25% higher thanthat reported by Wang. Of all the berries studied, strawberrieshad the highest ascorbate content. In agreement with the previousstudies, Kalt found that ascorbate had little effect on antioxidantcapacity.

Some researchers using measurement methods other thanthe ORAC assay have obtained different results with respectto antioxidant activity in fruits. Kahkonen et al. found no cor-relation between phenolic content and antioxidant activity.44

Their lab measured phenolic content by means of the Folin-Ciocalteu procedure and measured antioxidant activity by themethyl linoleate (MeLo) method. The Folin-Ciocalteu methoddoes not give an accurate estimate of phenolic content ofa food because any other reducing agent, such as ascorbic acid,will also reduce the F-C reagent. Thus, the results include morethan just the phenolic content. Berries of all types hadhigher phenolic content than other fruits, vegetables, and grains.The most highly colored berries had the highest phenolic con-tent. The antioxidant responses of phenolic compounds in theMeLo oxidation model vary markedly. Phenolic compoundsthat are more lipid soluble will show better antioxidantactivity with the MeLo method. Again, the more highly col-ored berries performed better than the strawberries in this sys-tem. Strawberries had higher antioxidant activity than apples,and all of the vegetables except beets and the skins of redpotatoes.44

A study by Heinonen et al. tested the in vitro antioxidantactivity of berry phenolics on human low-density lipoproteins(LDL) and lecithin liposomes. All of the berries tested inhibitedboth LDL and liposome oxidation, but strawberries exerted the

weakest effects. Strawberries had the highest content of ascorbicacid, which was also found to be a weak antioxidant in thissystem. The researchers pointed out that interpretation of theresults is hampered by the fact that this study tested the phenoliccompounds in their free forms, whereas they exist in berriesmostly bound to sugars.40

Antioxidant compounds take various forms and thereforehave different efficacy against the various types of oxygen freeradicals. Wang and Jiao studied the effectiveness of berriesagainst four types of reactive oxygen species: singlet oxygen,hydrogen peroxide, hydroxyl radical, and superoxide radical.Strawberries had the highest antioxidant activity against singletoxygen. Blackberries had the highest activity against the otherthree, while strawberries were second in potency.41

Oxidative stress is believed to be a risk factor for many of themost common chronic diseases that plague humans, includingcancer, cardiovascular disease, and chronic inflammatory dis-eases. For this reason, there is a great deal of interest in the pos-sibility that consuming a diet rich in antioxidant compounds mayreduce risk. First, however, the important question of whether ornot these compounds can be absorbed and utilized by humansmust be answered.

BIOAVAILABILITY OF PHENOLIC COMPOUNDS

The bioavailability of phenolic compounds in foods is deter-mined by their structure, size, solubility, degree of glycosyla-tion, and conjugation with other compounds. Until recently, itwas thought that little absorption of phenolic compounds wouldoccur because in most cases they are in the form of glycosides,i.e. bound to sugars. Only the aglycones were thought to be capa-ble of passing through the gut wall. It was believed that humansdo not produce an enzyme that can split the predominantly β-glycosidic bonds, and that flavonoids would therefore be poorlyabsorbed.45

Several researchers have studied the bioavailability ofquercetin, since it is the major flavonoid in the human diet.Hollman et al. found that significant amounts of quercetin wereabsorbed from onions in humans. Interestingly, 52% of thequercetin glycosides were absorbed from onions, as comparedto absorption of only 17% of a purified quercetin rutinoside and24% of quercetin aglycone.46 Although the bioavailability ofquercetin from foods can be quite a bit higher than from pu-rified compounds, it seems to depend upon the carbohydratemoiety associated with the flavonoid.47 A follow-up study bythese researchers found that absorption of quercetin from ap-ples was only half that from onions.48 Apples contain quercetinboth with and without a glucose moiety, while the quercetinin onions is almost entirely in β-glycoside form. Hollman hasspeculated that the greater availability of quercetin from onionsoccurs because of intestinal sugar carriers that actively transportβ-glycosides.46 Gee et al. have recently provided data in supportof this hypothesis.49 In any case, it is clear that bioavailability

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POTENTIAL IMPACT OF STRAWBERRIES ON HUMAN HEALTH 7

can differ markedly among foods, and that each food should betested individually.

Hollman’s results were based on measures of excretion. Incontrast, a study by Conquer et al. tested quercetin absorption bymeasuring plasma levels of quercetin in healthy subjects follow-ing consumption of a quercetin supplement.50 Plasma quercetinlevels reached 1.5 µmol/l (427 ng/ml) in response to one gramof quercetin, a level comparable to the concentration requiredto inhibit cancer cell growth in vitro.51 Of course, one gram ofquercetin is a much higher intake than the estimated averageof 25–40 mg/day. However, as was noted by Hollman, a purequercetin supplement is absorbed only half as well as quercetinglycosides from onions. In addition, the half-life of quercetin isabout 25 hours, which implies that people eating diets rich in thisflavonoid could easily maintain a high plasma level. Quercetinis apparently eliminated from the plasma more slowly than mostflavonoids, probably because of its very high binding affinity forplasma albumin.48

We now know that humans do in fact produce β-glycosidases,and that this enzyme is present on the outside of the brush bor-der membrane in the small intestine.52 This has implications forbioavailability of all the flavonoids. Bourne and Rice-Evans re-ported that hydroxycinnamates and flavonoids from a variety offruits are well absorbed.53

Cao and Prior found that the absorption of anthocyanins froman elderberry extract was reasonably good. Thirty minutes afterconsuming 25 g of the extract, the plasma level of total antho-cyanins in a 35-year-old male was 100 µg/l, which is equiva-lent to approximately 0.4 nmol/l.54 In another study, these re-searchers found that both anthocyanidin (aglycone form) andanthocyanin (glycated form) were absorbed in humans.55 In sup-port of these findings, Miyazawa et al. determined that certainanthocyanins are absorbed from the digestive tract into the bloodin their intact glycoside forms.56

A study of the absorption and splanchnic metabolism offlavonoids, including quercetin, kaempferol, and catechin,showed great variability in how the different compounds arehandled in the rat.57 The most lipophilic molecules, includ-ing quercetin and kaempferol, were more efficiently transferredacross the brush border than catechin, which is much lesslipophilic. Quercetin metabolites synthesized in the enterocyteswere copiously secreted back into the intestinal lumen. As aresult, only about 9% of the total quercetin was available forperipheral tissues as compared to 34% of the catechin.57

As was suggested by Hollman’s work with quercetin, the ab-sorption of flavonoids can also be influenced by the food matrixin which they are found. One could speculate that other foodseaten at the same time could also have an effect. Although littlework has been done in this area, researchers at the University ofCalifornia have demonstrated in human subjects that absorptionof flavanols from cocoa is enhanced by the presence of carbo-hydrate, but is not affected by the presence of protein and fat.58

The bioavailability of ellagic acid in humans is essentially un-known. Mice fed radio-labelled ellagic acid were found to absorb28% of the dose, or about 0.12 mg/kg body weight. The absorbed

ellagic acid was found in urine, bile, and blood. About half of itwas conjugated with sulphate, glucuronide or glutathione.59

There are no specific recommended intakes for the phenoliccompounds, since they have not been identified as required nu-trients. The average intake of total dietary phenolic compoundshas been estmated at 1 gram per day.15,60 Accurate data onfood intakes and food composition are not yet available. Epi-demiologists have suggested that the main sources of phenoliccompounds are tea, coffee, wine, chocolate, berries, apples, andonions. In certain Asian countries, soy foods contribute greatlyto the total phenolic consumption.15 The high phenolic contentof strawberries is evident when considering that one cup of freshfruit (149 g) would provide as much as 300 mg of total pheno-lics. This would include as much as 3 mg of ellagic acid and5 mg of quercetin, which is significant given that some studieshave shown this level of quercetin intake to be associated withprotection against lung cancer.61

STRAWBERRIES AND CANCER

Cancer chemopreventive agents can act at different stagesof the disease process, by inhibiting formation of carcinogens,blocking initiation of carcinogenesis, or suppressing progressionand proliferation of tumors. Some of the compounds in strawber-ries have been studied as possible anticancer agents. Althoughthe bioactivity of these compounds is not well understood, itappears that some may work by more than one mechanism.

Ellagic Acid

There is considerable interest in the potential anticancer ef-fects of ellagic acid. Researchers from Hollings Cancer Centerbelieve that enough evidence has accumulated to support a rolefor ellagic acid as a chemopreventive agent.62

Animal studies using chemical carcinogens have demon-strated that ellagic acid has anticancer effects in many cases,depending on the type of chemical used. Newborn mice weretreated with ellagic acid before receiving an injection of thecarcinogens benzo[a]pyrene (B[a]P) or benzo[a]pyrene diol-epoxide (BPDE). The researchers saw 44–75% fewer lung tu-mors in ellagic acid-treated mice compared to controls whenBPDE was the carcinogen, but little or no effect when B[a]P wasused.63 Chang’s group also tested the effect of topical applica-tion of ellagic acid before doses of B[a]P and BPDE, promotedwith 12-O-tetradecanoylphorbol-13-acetate (TPA), on the in-cidence of skin cancer in mice. Ellagic acid-treated mice had59–66% fewer skin tumors than controls when BPDE was used,and 28–33% fewer tumors with B[a]P.63 These findings provideevidence that ellagic acid may have a binding affinity for BPDEin vivo, as has been seen in vitro.64

In rats, dietary ellagic acid inhibited the development ofesophageal cancer induced by N -nitrosomethylbenzylamine(NMBA) by 25–50%. Both preneoplastic and neoplastic lesions

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were reduced.65,66 However, these researchers have noted thatthe tumor inhibition occurred only when the ellagic acid wasgiven continuously before, during and after the NMBA dose.There was no significant effect when the ellagic acid was givenonly in the post-initiation phase.67 Another rat study lookingat hepatic effects found that a diet containing 400 ppm ellagicacid given before, during, and after cancer initiation by N -2-fluorenylacetamide (FAA) significantly reduced markers of livercancer.68

These and other animal studies have shown that ellagic acidmay be protective against certain polycyclic hydrocarbons, in-cluding B[a]P and MCA,63,69–71 and against certain nitroso com-pounds, including NMBA and NNK 65–67 for cancers of the lung,skin, esophagus, and liver.

An in vitro study using the human breast cell line MCF-7tested the efficacy of several chemopreventive agents againstinitiation of carcinogenesis by dibenzo[a,l]pyrene (DBP). El-lagic acid at a dose of 30 µM inhibited carcinogenesis by 45%,which was similar to the effect seen with genistein.72 Ellagicacid has also been shown to inhibit mutagenesis by aflatoxin B1

in cell cultures of rat and human tissue.73

Researchers have begun to elucidate the possible mechanismsby which ellagic acid exerts its anticancer effects. In most cases,a potential carcinogen must first be activated to an electrophilicform in order to react with DNA, forming adducts that cause mu-tations. Ellagic acid is known to decrease the metabolic activa-tion of certain carcinogens by inhibiting microsomal cytochromeP450 enzymes in liver, lung, and esophagus.71,74–77 Aryton sug-gested that ellagic acid may be non-specific in its inhibition ofP450s.75 If this were true, it could interfere with normal P450functions such as steroid metabolism. However, Ahn’s researchdemonstrated conclusively that inhibition of P450s by ellagicacid is specific. In rats fed dietary ellagic acid, at both 0.4 and4.0 g/kg, significant reduction was seen in hepatic P450 2E1,but not in the other forms.76 In rats and humans, P450 2E1is the principal enzyme known to activate certain carcinogens,including nitrosamine, aniline, chlorinated hydrocarbons andbenzene.78

Another mechanism by which ellagic acid may interfere withcarcinogenesis is by inducing hepatic phase II detoxifying en-zymes, including glutathione S-transferase (GST), NAD(P)H:quinone reductase [NAD(P)H:QR], and UDP glucuronosyl-transferase (UDPGT).70,76,79,80 The effect of ellagic acid onphase II enzymes appears to be tissue-specific. In rats, dietary el-lagic acid increased hepatic GST activity by 26%, NAD(P)H:QRby 17%, and UDPGT by 75%. Individual isoforms of GST wereincreased dramatically, ranging from 80% (for 5-5) to 190% (for2-2). However, in the same animals esophageal activity of 2-2GST was decreased by 66%.76

A third mechanism by which ellagic acid may inhibit cancerinitiation is by scavenging oxygen free radicals and the reactivemetabolites of carcinogens. For example, BPDE, the reactivemetabolite of B[a]P, becomes harmless after bonding with el-lagic acid because the epoxide ring is opened.63,64,81 Oxygenfree radicals are produced by the metabolism of carcinogens

and by inflammatory cells. These free radicals can produce DNAstrand breaks and mutations, and subsequent carcinogenesis.82

Ellagic acid is a potent antioxidant that can inhibit this process.Oxygen free radicals are also produced by ionizing radia-

tion. In addition, radiation can be a direct cause of DNA strandbreaks. One study investigated the protective effect of ellagicacid against whole body radiation exposure in mice. Oral ad-ministration of 200 µmol/kg of ellagic acid significantly reducedthe number of DNA strand breaks and chromosomal aberrationsseen in the treated mice compared to controls.83

An additional way in which ellagic acid may block cancerinitiation is by binding to DNA, occupying sites that would oth-erwise be vulnerable to attack by carcinogens.84,85 In one ratstudy, the researchers hypothesized that dietary ellagic acid in-hibited initiation of cancer by NMBA by selectively blockingmethylation of the O6 position of guanine.86

In addition to the many mechanisms by which ellagic acid hasbeen shown to inhibit cancer initiation, there is evidence that itmay also suppress tumor promotion in some cases. The neoplas-tic capability of cells is correlated with their polyamine content.A key enzyme in the production of polyamines is ornithine de-carboxylase (ODC). In fact, tumor cells have particularly highlevels of ODC and polyamines. In mice, numbers of skin tumorsinduced by B[a]P and promoted by TPA were reduced in thosetreated with topical ellagic acid.63 Perchellet confirmed this find-ing, and suggested that ellagic acid suppresses TPA-inducedODC activity, hydroperoxide production and DNA synthesis, allof which are markers for tumor promotion.87 Dietary ellagic acidsignificantly reduced the incidence of tongue neoplasms inducedby 4-nitroquinoline-1-oxide (4-NQO) in rats. Measurement ofsilver-stained nucleolar organizer region proteins (AgNORs), amarker of cell proliferation, showed a reduction in both numberand area of lesions.88 Ellagic acid also suppresses tumor growthby inhibiting DNA topoisomerases I and II (topo I and II).89

Topo I and II are necessary for DNA replication, and therefore,cell proliferation.

Since ellagic acid has so many bioeffects, it is reasonableto question whether it could be toxic at high intakes. How-ever, data are sparse and inconsistent on the possibility of tox-icity of ellagic acid. In one rat study, 100 mg/kg ellagic acidwas given by intraperitoneal injection, in order to bypass theproblem of limited absorption. At autopsy, these animals wereshown to have severe liver damage, which the researchers spec-ulated could have been caused by non-selective destruction ofhepatic P-450 by the ellagic acid.75 It would be virtually impos-sible for humans to attain doses of ellagic acid this high throughdiet. In fact, it may even be difficult to consume the amount ofellagic acid found to be protective in animal studies. Cliffordand Scalbert calculated that a 65 kg adult would have to con-sume 260 mg of ellagic acid per day to achieve the levels used inmost animal studies, while the current intake appears to be about.02% of this amount.90 On the other hand, Ahn’s study foundthat doses of 0.4 and 4.0 g/kg were equally effective and safe,76

indicating that ellagic acid is efficacious over a large range ofintakes, at least in rats. At this point, there are clearly not enough

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data to recommend either minimum or maximum intake levelsfor humans.

Flavonoids

The main flavonoids present in strawberries are anthocyanin,catechin, quercetin and kaempferol. All of the flavonoids areknown to be potent antioxidants and therefore have protectiveeffects similar to those of ellagic acid by scavenging oxygen freeradicals.

Anthocyanins, especially certain isoforms such as cyanidin3-O-β-D-glucoside (C3G), have been shown to be particularlypotent antioxidants and scavengers of hydroxyl radicals and su-peroxide in in vitro studies91,92 and in ex vivo serum from ratsfed C3G.93 Few studies have looked at specific anticancer effectsof anthocyanins, but the results have been encouraging. One invitro study found that anthocyanins suppressed the growth ofcolon cancer cells.94 In this study, certain anthocyanins wereeffective at a concentration of only 2 µg/ml, which is 1/10 theconcentration required for an effect by the known anticarcinogengenistein.

In a mouse model of DMBA-induced skin cancer, a highproanthocyanidin extract from grape seeds inhibited TPA-induced promotion of tumors.95 The researchers determinedthat the mechanism was by inhibition of ODC and protein ki-nase C, which resulted in suppression of cell proliferation anddifferentiation.95,96 In a dual-organ study, female rats fed grapeseed proanthocyanidins at doses ranging from 0.1 to 1.0% of thediet experienced a 72–88% inhibition of AOM-induced colonaberrant crypts, and a 20–56% inhibition of ODC activity in thedistal colon.97 However, no significant effect was seen on theactivity of P450 2E1 in liver, or on DMBA-induced mammarytumorigenesis.

Catechin has also been studied as a potentially chemopro-tective compound. As a cancer model, HTLV-1 tax transgenicmice spontaneously develop tumors without treatment with acarcinogen. When 4 mmol catechin/kg diet was fed to transgenicmice, the onset of tumor development was delayed by 45%.98

Seeram et al. evaluated the ability of anthocyanidins and cate-chins to inhibit proliferation of several human cancer cell lines,including MCF-7 breast, SF-268 central nervous system, HCT-116 colon, and NCI-H460 lung cancer cells.99 They concludedthat only the galloyl derivatives of catechins were effective atinhibiting proliferation of these cancer cell lines. Interestingly,of the 29 types of fruit analyzed by Pascual-Teresa et al., gal-loyled catechins were detected in only strawberry, medlar, andgrape,34 although Arts et al. did not find any in their analyses.33

Indeed, the form of catechin that has been studied most exten-sively in cancer research is epigallocatechin gallate (EGCG).The vast majority of the work in this area has been on tea,since EGCG is the major active compound in this popular bever-age. A recent study demonstrated that EGCG inhibits productionof telomerase, an enzyme which plays a role in immortalizingtumor cells.100

Quercetin has been studied extensively for its potential anti-cancer effects. Like ellagic acid, quercetin has been found to in-hibit chemically-induced carcinogenesis in several animal mod-els, including: DEN-induced lung cancer in mice;101 4-NQO-induced tongue cancer in rats;102 DMBA-induced skin cancerin mice;103 DMBA-induced cancer in hamster buccal pouch;104

DMBA- and nitrosomethylurea (NMU)-induced rat mammarycancer;105 and azoxymethane (AOM)-induced colon cancer inmice.106 Another study failed to find an anticarcinogenic effectof quercetin on DMBA-induced rat mammary cancer and saw apossible enhancing effect on AOM-induced colon cancer.107

In one interesting study, rats were treated with several car-cinogens and were fed quercetin at 1% of the diet both before andafter the induction phase. The effects of quercetin on several dif-ferent organ systems were tested. Quercetin significantly inhib-ited adenomas and carcinomas in the small intestine, but effectsin the other organs were not significant.108 Dietary quercetin atonly 0.05%, fed during either initiation or promotion, inhibited4-NQO-induced tongue carcinoma.102 In this study, quercetinwas found to decrease polyamine levels and cell proliferation,similar to what is seen with ellagic acid. Quercetin also has beenshown to suppress TPA-induced promotion of tumors in mouseskin.103 Quercetin injected intraperitoneally in mice suppressedmelanoma cell growth and metastasis.109

Some mechanisms of action have been elucidated forquercetin. Similar to ellagic acid, quercetin has been shown toinhibit formation of DNA adducts with B[a]P, thus blocking theactivation of certain carcinogens.110,111 Kaempferol was alsoshown to block formation of these adducts.110

Cell culture studies with quercetin have resulted in some in-teresting new findings. Quercetin inhibits the growth of humanprostate cancer cells112 and human breast cancer cells at picomo-lar concentrations.113 Earlier work proposed that quercetin in-hibits tumor growth by interacting with estrogen binding sites.114

This was later confirmed in a study which showed that quercetincompeted for estrogen binding sites in leukemia cells.115 Fur-thermore, Scambia showed that quercetin inhibited the growthof human ovarian cancer by stimulating ovarian cells to pro-duce transforming growth factor β1, which is an antiproliferativeagent.116

An additional anticancer benefit of quercetin is that it has beenshown to promote apoptosis, or programmed cell death, in dam-aged cells.117–119 Wei suggested that quercetin enhances apop-tosis by inhibiting the synthesis of heat shock protein (HSP) 70,which is involved in regulation of cell proliferation.117 Quercetininduced apoptosis in colorectal cancer cells118 and in skin can-cer cell lines.119 Inhibition of epidermal growth factor (EGF)receptor tyrosine kinase activity was suggested as a possiblemechanism.118,119 Kaempferol was also tested in Richter’s sys-tem and was found to be less active than quercetin.118

Gerhauser et al. studied 22 different cancer chemopreventivecompounds in a battery of ten in vitro assays designed to demon-strate the mechanisms by which the agents work.120 Two assaysidentified effects on modulators of carcinogen metabolism, fiveevaluated radical scavenging and antioxidant activity, and three

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tested for anti-inflammatory and anti-tumor mechanisms. In-cluded in the study were three of the bioactive compounds instrawberries: ellagic acid, quercetin, and catechin (in the formof EGCG). Quercetin was shown to be the most effective chemo-preventive agent of all 22, with positive results in nine of the tenassays. Ellagic acid and EGCG both performed well in radicalscavenging and antioxidant activity.120

In the 1970’s quercetin and kaempferol were reported tobe mutagenic to S. typhimurium as determined by the Amestest.121 However, these compounds apparently are not muta-genic in mammals in vivo.122 Possible enhancement of AOM-induced colon cancer in rats by quercetin has been reportedmore recently.107 However, rats fed dietary quercetin at 1.25%and 5% of the diet for two years showed no carcinogenicity.123

In a similar study rats were fed a very high dose of quercetinfor two years, and the researchers found only benign tumors ofthe renal tubular epithelium.124 Overall, the vast majority of re-search on this question has shown that the effects of quercetinare anticarcinogenic.125 At this point, we do not have enoughinformation to define a safe and effective dose for humans.

Whole Strawberries

Epidemiological studies have clearly shown that consump-tion of fruits and vegetables is associated with lower cancer risk.1

It is reasonable to believe that strawberries help contribute tothis health benefit, based on what we know about their bioactivecomponents. However, studies using pharmacological doses ofindividual compounds isolated from the berries may not neces-sarily be relevant to human health. In order to gain a meaningfulunderstanding of the potential anticancer effects of this food, itis important to investigate the effects of whole strawberries.

Clastogens, such as cyclophosphamide (CP) and benzo[a]-pyrene (B[a]P), cause chromosomal breaks, which can then leadto cancer. Edenharder et al. investigated the anticlastogenic ca-pacity of extracts from several fruits and vegetables.126 Micewere fed a plant extract, were either injected with B[a]P or orallyadministered CP, and then were killed 48 hours after dosing withthe clastogens. Bone marrow cells were isolated from the miceto quantify chromosomal breaks. Table 7 shows the results ofEdenharder’s study. Strawberries caused a moderate inhibitionof B[a]P, and a weak inhibition of CP.126

Stoner’s group found that a freeze-dried strawberry prepara-tion at 5% or 10% of the diet, fed continuously before, duringand after treatment, inhibited NMBA-induced esophageal can-cer in rats in a dose-dependent manner.127 The researchers notedthat the inhibitory effects of the strawberries were greater thanwould be expected from ellagic acid alone. The inhibition in-duced by the 10% strawberry diet, which provided 0.67 g/kgellagic acid, was greater than that seen with 4 g/kg of pureellagic acid.65,127 However, when mice were fed a 10% straw-berry diet before, during and after treatment with the carcinogens4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) andB[a]P, there was no difference in lung tumor incidence between

Table 7 Antimutagenic/anticlastogenic effects of fruits and vegetables

Clastogen

Cyclophosphamide Benzo(a)pyrene

MNPCEs/ Anticlastogen MNPCEs/ AnticlastogenicProduct 3000 PCEs potency 3000 PCEs potency

Apples 40.83 − 12.08 −Bananas 29.38 ++ 2.69 +++Cherries, sweet 38.25 + 6.75 ++Kiwi 43.94 + 3.69 +++Oranges 22.58 ++ 8.25 ++Peaches 21.92 ++ 8.25 ++Strawberries 41.19 + 9.50 +Asparagus 32.91 ++ 7.92 −Beets, red 24.50 ++ 8.42 ++Brussels sprouts 32.75 − 10.00 +Cauliflower 43.92 − 10.33 −Cucumber 37.75 + 6.75 ++Onions 49.00 − 11.42 −Peppers, 16.75 +++ 10.08 −

yellow-redRadish 36.83 + 8.42 +/++Spinach 15.33 +++ 7.33 ++Tomatoes 30.25 + 13.00 −

− No inhibition, + weak inhibition, ++ moderate inhibition, +++ stronginhibition.

Edenharder et al., 1998.126

the controls and the strawberry group.128 The lack of effect couldbe due to the type of carcinogen used, the cancer site, or a dif-ference between rats and mice with regard to bioavailability ofthe effective compounds.

In another study with rats, Stoner et al. reported that straw-berries apparently inhibited both initiation and promotion byNMBA. Freeze-dried strawberries added to the diet only afterinitiation of cancer inhibited the progression of simple leuko-plakic lesions to dysplastic leukoplakia.129 As mentioned pre-viously, ellagic acid alone has not been shown to be effectiveagainst cancer promotion by NMBA,67 so it is clear that straw-berries contain other factors that provide protection against can-cer promotion.

A cell culture study using two varieties of freeze-dried straw-berries tested the ability of these fruits to inhibit the growth oftwo types of breast cancer and two types of cervical cancercells.130 Both varieties of strawberry significantly inhibited thegrowth of both types of cervical cancer cells. Both varieties alsoeffectively inhibited both types of breast cancer cells, althoughSweet Charlie was more potent than Carlsbad.

Another study with freeze-dried strawberries analyzed theeffects of different fractions of the strawberries on cell transfor-mation in the Syrian hamster embryo (SHE) model.131 As ex-pected, the fraction containing ellagic acid inhibited cell trans-formation by B[a]P in both a 24-hour co-treatment and in a6-day treatment following 24 hours with B[a]P alone. In addi-tion, a methanol extract containing other compounds from theberries, but no ellagic acid, inhibited the cell transformation inthe 24-hour co-treatment only.131 This confirmed the existence

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of other anticancer compounds in the strawberries besides el-lagic acid.

N-nitrosodimethylamine (NDMA) is a carcinogenic com-pound produced endogenously by humans consuming excessiveamounts of nitrates. An in vivo experiment tested the ability ofstrawberries to inhibit NDMA formation in healthy subjects fedan amine-rich diet plus 400 mg of nitrate. Urinary concentrationof NDMA was decreased by 70% when 300 g whole strawberrieswere consumed with the test meal.132

It is known from numerous in vitro studies that strawberrieshave tremendous antioxidant capacity.∗ In a recent study, poten-tial in vivo effects were examined by measuring serum and urineantioxidant capacity in elderly women following consumption of240 g strawberries, 294 g spinach, 300 ml red wine, or 1250 mgvitamin C.135 All of these items increased antioxidant capacity ofserum and urine, with spinach providing the highest values, fol-lowed by vitamin C, strawberries, and red wine. The researchersconcluded that a large portion of the antioxidant capacity fromspinach, strawberries and red wine came from phenolic com-pounds in these foods rather than from their vitamin C content.Since antioxidant capability is an important anticancer weapon,strawberries would be considered good candidates for scaveng-ing free radicals, thereby reducing the risk of DNA damage andcarcinogenesis.

STRAWBERRIES AND CARDIOVASCULAR DISEASE

In epidemiological studies, consumption of fruits and vegeta-bles, particularly those high in flavonoids, has been associatedwith lower risk for heart disease as well as cancer.136–138 Theantioxidant capacity of flavonoids has been cited as one of themain reasons for the health benefits of these foods. The foodcomposition data that were available at the time of these stud-ies listed only five of the flavonoids, including quercetin andkaempferol. Since strawberries are rich in other phenolic com-pounds that were not included, such as anthocyanin, catechin,and ellagic acid, their potential contribution may be greater thanpredicted from the epidemiological data.

Antioxidant power is important in the prevention of heart dis-ease, since oxidation of low-density lipoprotein (LDL)-cholesterol is one step in the progression of atherosclerosis.There is evidence that antioxidants help lower risk of cardiovas-cular events in several additional ways, including promotion ofplaque stability, improved vascular endothelial function, and de-creased tendency for thrombosis.139 The “French paradox,” thelow incidence of heart disease in France despite the consumptionof a high fat diet, may be partly attributed to the popularity ofred wine, which is high in antioxidant power from anthocyaninsand catechins.140–142

An interesting in vitro study investigated the effects of fiveindividual phenolic compounds on human LDL oxidation, aswell as the interactions among the compounds.143 Catechin,

∗See references 31, 32, 39, 40, 41, 43, 44, 133, and 134.

quercetin, cyanidin and caffeic acid all exhibited antioxidanteffects, but ellagic acid showed little or no effect in this system.The compounds were studied in combinations of two or three.No synergistic effect was seen among the phenolic compounds,but an apparent antagonistic effect was seen between catechinand ellagic acid.143

Another in vitro study investigated the effects of various berryextracts on oxidation of human LDL and lecithin liposomes.40 Ata concentration of 10 µM gallic acid equivalents (GAE), acetoneextracts from strawberries inhibited oxidation of human LDL by53.9%, and a 20 µM concentration inhibited by 86.1%. In theliposome system, the 10 µM extract inhibited hydroperoxideformation by 27.4%, and the 20 µM inhibited by 42.8%. Of theberries tested, the most potent effects on LDL oxidation wereseen with blackberries, and the most potent effects on liposomeperoxidation were by sweet cherries.40

Certain flavonoids that occur in strawberries have been shownto inhibit platelet aggregation, including quercetin, kaempferol,catechin, and anthocyanins.144,145 These flavonoids apparentlyact by inhibition of thromboxane synthesis. This activity resultsin a decreased tendency to form thrombi, thus reducing risk ofstroke. On the other hand, ellagic acid is known to promote bloodcoagulation, by activation of the Hageman factor.146 It would beinteresting to study the overall effect of whole strawberries onblood clotting.

Quercetin and kaempferol have also been found to inhibit therelease of mast cells in animal studies.147,148 Since mast cellsare involved in cardiovascular inflammation149 this is anotherimportant activity of these flavonoids that may help reduce riskof heart disease.

The individual components of strawberries appear to havegreat potential for reducing the risk of cardiovascular disease,and we know that humans respond well to diets rich in fruits andvegetables. In a recent well-controlled clinical trial, 123 healthypersons who were fed a diet containing nine servings per day offruits and vegetables significantly increased serum antioxidantcapacity and decreased in vivo lipid peroxidation.150 This studyprovides direct support for the epidemiological data linking fruitand vegetable consumption with heart health. Another studywas carried out in diabetic patients, who are known to have re-duced antioxidant defense and a greater risk of heart disease.151

Just two weeks on a diet high in flavonols, mainly quercetin,demonstrated a protective effect against oxidative damage toDNA in lymphocytes.151 In light of the literature reviewed here,it would be worthwhile to conduct clinical trials to investigatethe specific effects of strawberry consumption on heart health.

OTHER HEALTH EFFECTS OF STRAWBERRIES

In addition to the decrease in risk for cancer and heart dis-ease, the phenolics in strawberries have effects on the immunesystem that may be important in the prevention of a variety ofconditions. Seeram et al. recently studied the effects of cyani-din extracts from cherries and berries on cyclooxygenase (COX)inhibition in vitro.152 COX is a key enzyme in the conversion

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of arachidonic acid to the various eicosanoids involved in in-flammation. COX inhibition is the means by which aspirin andother non-steroidal anti-inflammatory drugs (NSAIDs) work.There are two isoforms of COX, COX-1 and COX-2. Extractsfrom strawberries were moderately effective in inhibiting COX-1, and were more potent inhibitors of COX-2 than all the otherberries except blackberries and sweet cherries.152 COX-2 is themain promoter of inflammatory prostaglandins, while COX-1 is known to produce some gastroprotective prostaglandins.Therefore, there may be some advantage to selectively inhibit-ing COX-2. Interestingly, strawberries were half as effective atinhibiting COX-1 as the NSAID controls, but were more effec-tive than these drugs at inhibiting COX-2. These findings areimportant because the inflammatory process is involved in theetiology of a wide range of diseases, including cancer,153 heartdisease,154 and Alzheimer’s disease.155

Other phenolic compounds present in strawberries have alsodemonstrated effects on the immune system. Quercetin andkaempferol have both been shown to inhibit the release of mastcell histamine.148 Mast cells are involved in the pathogenesis ofasthma and allergic reactions. Antiviral activity has also beendemonstrated by quercetin against several types of viruses.156

Ellagic acid has an inhibitory effect on Helicobacter pylori iso-lated from peptic ulcer patients.157

The possibility that phenolic compounds may help preventneurological problems in the brain is an intriguing idea for whichevidence is emerging.158 In one study, the diets of rats were sup-plemented with spinach, strawberry, or vitamin E for 9 months,from adulthood through middle age.159 Various indicators ofbrain function were measured. Strawberry had the greatest effecton signal transduction assessed by GTPase activity. Strawberryand vitamin E showed equal protective effects on several mea-sures of age-related deficits.159 Bickford et al. fed diets enrichedwith spinach, blueberries, or strawberries to aged rats and studiedthe effects on motor learning and memory.160 All three enricheddiets had equal antioxidant activity, as measured in Trolox equiv-alents. All three of these diets reversed age-induced declines inperformance of the animals on a motor learning test. In addition,the rats were tested for response to a β-adrenergic agonist. Nor-mally, 75–80% of neurons in young animals will respond, whileonly 40% in aged animals do. On the enriched diets, the aged ratshad a 65–68% response.160 Finally, levels of glutathione in thecerebellum were measured. Levels were significantly increasedin the rats fed strawberry or blueberry, indicating a healthy re-sponse to oxidative stress. Glutathione levels in the spinach-fedanimals were increased, but not significantly.160

SUMMARY OF STRAWBERRIES ANDHEALTH EFFECTS

Strawberries are rich in a variety of phytochemicals that havebeen shown to be bioactive. Studies of the individual compoundshave demonstrated anticancer activity, blocking initiation of car-cinogenesis, and suppressing progression and proliferation of

tumors. For ellagic acid and quercetin, there is a huge body ofliterature on this topic. In many cases, their specific mechanismsof action are now understood.

Because of the antioxidant power of the phenolic compoundsin strawberries, consumption of this fruit may well have thepotential to lower risk of heart disease. Studies of the individualcomponents have demonstrated inhibition of LDL oxidation andlipid peroxidation, and suppression of inflammation.

Animal studies have indicated that the antioxidant activityof strawberries also has the potential to provide benefits to theaging brain.

Inhibition of the COX enzyme by strawberries has beendemonstrated in vitro. This is potentially an enormously im-portant finding, since the inflammatory process is involved inthe etiology of many diseases.

RECOMMENDATIONS FOR FUTURE RESEARCH

There is a great deal of research evidence on the health ben-efits of fruits and vegetables in general, and of specific foodcomponents found in strawberries. However, there are very fewdata on the effects of strawberries on human health. Based onthe encouraging findings to date, the following research work isrecommended:

• More clearly establish the content of phenolic compounds instrawberries and compile a chromatographic fingerprint to beused in research.

• Establish the bioavailability of the various phytochemicalsfrom strawberries through human feeding studies. In addi-tion, identify the metabolites of these compounds and theirbioactivity.

• Develop a standard strawberry product to be used in research.It should have a consistent phytochemical profile, be appro-priate for consumption by humans, and be stable for at least ayear.

• Continue cell culture studies to elucidate the mechanisms ofaction for the phenolic compounds in strawberries.

• Study the effect of strawberry consumption on specificbiomarkers for heart disease in animals and humans: serumand urine oxidative capacity; LDL oxidation and lipid perox-idation; vascular endothelial function (by brachial artery ul-trasound). In human research, both healthy and compromisedpopulations, of both genders and all ages, should be studied.

• Study the effect of strawberry consumption on specificbiomarkers for cancer in animals: measures of phase II en-zymes, formation of DNA adducts, oxidative DNA damage,cell proliferation. In order to keep the animal studies as rele-vant as possible to humans, reasonable dietary levels shouldbe used.

• Conduct long-term prospective cancer studies in humans, fo-cusing on the effects of strawberry consumption. More accu-rate dietary consumption data are needed, in addition to moredetailed food composition data.

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ACKNOWLEDGEMENT

This literature review was supported in part by the California StrawberryCommission.

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