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Cranberry

GlossarySuccess Chemistry Staff

Cranberry (Vaccinium macrocarpon Aiton) is a native plant of North America. Today, it is one of the top selling herbal supplements in the U.S. market.

Juice and dietary supplements derived from the berry reportedly exhibit various

health benefits, including prevention and treatment

of bacterial adhesion in urinary tract infections (UTIs)

and stomach ulcers, prevention of dental caries, protection

against lipoprotein oxidation, and anticancer activity.

Some of these biologic effects have been linked to the presence

of phenolic compounds. The composition of these

compounds in cranberry is beginning to be assessed and

quantified; however, their bioavailability and metabolism

are for the most part not known. Interpretation of results

from research on the efficacy/safety profile of cranberry

is confounded by methodologic limitations. More

research is needed to conclusively determine its health

benefits.

BACKGROUND

V. macrocarpon Aiton, the cultivated species, is a member

of the heath family (Ericaceae), which includes blueberry,

huckleberry, and bilberry. The wild plants are distributed

over eastern United States and Canada. Cranberry was of

great economic value to the Native Americans, especially

since it was the only edible fruit available late in the season

(September–November). Various parts of the plant were

used as dyes, food, and medicines. They used the berries

in poultices for treating wounds and blood poisoning; the

leaves for urinary disorders, diarrhea, and diabetes; and

infusion of branches for pleurisy (1). In addition, the European

settlers applied cranberries therapeutically for the relief

of blood disorders, stomach ailments, liver problems,

vomiting, appetite loss, and cancer. Sailors took barrels

of the fruit to sea to prevent scurvy. Over 100 years ago,

women in Cape Cod were known to use it for the treatment

of dysuria. About four decades back, consumption

of the berry for treatment of UTI received attention and

support within the medical community (2,3).

Cranberry was first cultivated in the early 19th century.

The principal areas of cultivation in North America

are Wisconsin, Massachusetts, New Jersey, Oregon, and

Washington, as well as parts of Canada. In the 1940s,

cranberry juice cocktail became widely available and is

the most common form of cranberry consumption today

(1). This is a sweetened beverage of about 27% cranberry

juice by volume. As a dietary supplement, cranberry ranks

among the top 10 selling herbal products in the U.S. market,

with U.S. sales skyrocketing in 2007 by 15% (4). Also

in 2007, cranberry supplements were among the top 20

supplements used by adults and children, who used nonvitamin,

nonmineral, natural products for health reasons

(5). Concurrent with increasing sales, publication of original

scientific results, papers, and reviews almost doubled

between 2004 and 2009 compared to the previous five-year

period.

CHEMISTRY AND PREPARATION OF PRODUCT

The chemical composition for the nutrient constituents

(Table 1) of cranberry has been well documented (6,7).

Raw cranberries are relatively low in sugar content and

minerals compared to other small fruits. They are a very

good source of vitamin C, have a fair amount of vitamin

A, but are relatively low in the B vitamins.

Most of the biologic effects of cranberry have been

linked to its high level of phenolic compounds (8–11),

higher than 20 other fruits tested (12,13). The major phenolics

in the berry are flavonoids and phenolic acids. Chen

et al. (11) found a total of 400 mg of total flavonoids

and phenolic compounds per liter of sample in freshly

squeezed cranberry juice. About 44% were phenolic acids

and 56% flavonoids.

Phenolic acids include the cinnamic acids (C6–C3)

and benzoic acids (C7). Cinnamic acids occur naturally in

combination with other compounds, usually in the form

of esters. The ester of caffeic with quinic acid is a classic

example. On the contrary, benzoics usually occur as free

acids. Benzoic acid is the major “phenolic” compound in

cranberry (11). The fruits’ astringency is attributable to

high levels of organic acids, primarily quinic, citric, malic,

and benzoic.

Cranberries contain three major subclasses of

flavonoids: flavanols, flavonols, and anthocyanidins

Flavanols exist in the monomer form (catechin and

epicatechin) and the oligomer or polymer form (proanthocyanidins).

Proanthocyanidins, also known as condensed

tannins, are polymeric compounds, the basic structural

elements of which are polyhydroxyflavan-3-ol units

linked together by carbon–carbon bonds (14). Unlike

most fruits, cranberry contains a relatively high proportion

of A-type proanthocyanidins. One subclass of

proanthocyanidins is procyanidins.

and standardization of the bioactive constituents in

cranberry products are needed to help in determining

product stability and to allow comparison among studies.

However, quantification is not always straightforward.

A broad spectrum of methods is used to quantify the

constituents, leading to differing results. Finally, no

cranberry-standardized reference materials to which

results of different analytic methods can be compared are

available (22,23).

PRECLINICAL STUDIES

Bioavailability

The structural diversity of cranberry components has a

major influence on their bioavailability, which in turn influences

their biologic effects. Many studies have ignored

their achievable plasma concentration after ingestion as

well as the possibility of conjugation and metabolism of

bioactive components. In general, polyphenols reaching

the colon are extensively metabolized by microflora into

a wide array of low-molecular-weight phenolic acids. The

concentration of intact polyphenols (parent compounds

and their conjugated forms) in plasma rarely exceeds

1 mol/L (1 M) after consumption of a single compound.

However, measurement of plasma antioxidant

capacity suggests that more phenolic compounds are

present, largely in the form of unknown metabolites, produced

either in the tissues or by gut microflora. Their

urinary recovery has been found in the range of 1% to

25% of ingested amount (21).

The bioavailability of the major flavonoids from

cranberry has not been studied. However, their bioavailability

fromother dietary sources (e.g., tea, cocoa or chocolate,

red wine, onions, or fruits) has been analyzed (24–26).

Less is known about absorption and metabolism of the

proanthocyanidins than other flavanols, in part due to

their complex structures and nonspecific analytic methods

to detect them. Higher molecular weight polymers

are considered to have poor absorption (27,28). Proanthocyanidins

are degraded to low-molecular-weight metabolites

by human colonic microflora (29). Although biologic

activity is apparent after proanthocyanidin ingestion, only

its metabolites have been measured in the urine and

plasma (29).

Urinary Acidification

Cranberries contain quinic acid, which is excreted in the

urine as hippuric acid. Early studies attributed the antibacterial

nature of the fruit to the urinary acidifying activity

due to the excretion of organic acids and increased

concentration of hippuric acid (30–32). Other experiments

showed no decreased pH, nor increased levels of hippuric

acid or only a brief effect (33–35). Hippuric acid does have

antibacterial effects if present in acidic urine (pH 5.0) and

at concentrations of 0.02–0.04 M. However, cranberry juice

rarely can achieve the bacteriostatic concentrations by itself

without the addition of exogenous hippuric acid to

the diet (36,37).

 Flavonoid Content of Vaccinium macrocarpon (mg/100 g)

Anthocyanidins Flavanols Flavonols Proanthocyanidins

Source Cyanidin Peonidin (−)-Epicatechin (+)-Catechin Myricetin Quercetin Monomers Polymers

Cranberries, raw 41.81 42.10 4.37 0.39 6.78 15.09 7.26 233.48

Cranberry juice cocktail 0.38 NA NA 0.19 0.51 1.27 0.56 8.33

NA, Not applicable.

Source: From Refs. 8, 9.

Cranberry 195

Antiadhesion in Urogenital Infections

In vitro and ex vivo studies indicate that cranberry products

prevent adhesion of bacteria to the cell walls of the

urinary tract, thus preventing UTIs. Emphasis has been

on the role of components that act by interference with

bacterial adherence of Escherichia coli to uroepithelial cells

(38–40). Several ex vivo studies found antiadherence activity

in mouse and human urine (15,38,41–43). Two compounds

were identified that inhibited adherence. One was

fructose and the other was a nondialyzed polymeric compound

present only in cranberry. While fructose in vitro

inhibits adherence (38,40), it is unlikely to contribute to

in vivo antiadhesion activity in urine because it is metabolized

before reaching the urinary tract. The nondialyzed

polymeric compound proved to be A-type proanthocyanidins.

This compound, but not B-type dimer or the

(−)-epicatechin monomer, prevented uropathogenic E. coli

from adhering to uroepithelial cells in vitro (14,39,44).

Subsequently, isolated proanthocyanidins and

whole cranberry products have been shown to inhibit

E. coli adherence to model systems of primary cultured

bladder and vaginal epithelial cells in a dose-dependent

fashion, including clinically achievable doses (240 mL

cranberry juice cocktail). However, only a very small portion

of a dose may reach the bladder (45) and possibly

not even excreted intact in the urine (46). A new group of

urinary marker compounds, discovered by a robust antiadhesion

assay, include two new coumaroyl iridoid glycosides

and a depside (47). Furthermore, it is not known

if any cranberry constituents reach vaginal tissues (45).

In conclusion, to date no specific antiadherent cranberry

constituents or metabolites, proanthocyanidin or

otherwise, in the urine have been elucidated, and possible

synergism among constituents needs to be considered.

Dental Plaque

Cranberry compounds, alone or combined, may have the

potential to inhibit the development of dental plaque

(biofilm) and to prevent or reduce the severity of periodontal

disease. Nondialyzable, high-molecular-weight cranberry

compounds (anthocyanins and proanthocyanidins

in combination) may limit extracellular matrix degradation

and other pathologic processes leading to periodontal

disease. In vitro studies of this test material showed it

having a high capacity to inhibit proteolytic enzyme activity

of specific metalloproteinases and elastase, as well

as to inhibit production of metalloproteinases (48). These

enzymes play a major role in gingival tissue destruction,

connective tissue remodeling, and alveolar bone resorption.

Their secretion from host cells may, in part, be stimulated

by components of the dental biofilm.

The pathogenesis of dental caries involves an interaction

of diet constituents with microorganisms, which

occurs within dental plaque. Streptococcus mutans is considered

the primary microbial agent in this pathogenesis.

It has two virulent traits: (i) synthesis of extracellular

polysaccharides (glucans) through glucosyltransferases,

and (ii) ability to produce and tolerate acids, both of which

lead to cariogenic biofilms. Cranberry juice, crude extracts,

and semipurified materials composed of low- and/or

high-molecular-weight compounds have been shown in

vitro to disrupt the virulent traits of S. mutans and

Porphyromonas gingivalis (49–52). Eleven isolated, highly

purified, low-molecular-weight cranberry constituents

(including flavonols, phenolic acids, and proanthocyanidins)

were tested alone and in combination to investigate

which compounds influenced the virulence properties of

S. mutans associated with glucan synthesis and acidogenicity

(53). Phenolic acids showed little effect. However,

specific flavonoids and proanthocyanidins resulted

in moderate, statistically significant effects. Furthermore,

certain combinations of these low-molecular-weight compounds

appeared to have an additive effect.

Helicobacter pylori Infection

Several mechanisms by which cranberry constituents may

prevent or treat Helicobacter pylori infections have been examined

and hypothesized, including (i) interference of

bacterial adhesion, (ii) inhibition of cell growth and/or

colonization, (iii) exerting bactericidal activities, (iv) induction

of the bacteria to develop a coccoid (spheroid)

form, and (v) neutralization of gastric pH.

Adhesins mediate adhesion of H. pylori to epithelial

cells. Because cranberry or its constituents have been

shown to inhibit adherence of E. coli to uroepithelial cells

in vitro, it has been hypothesized that it would prevent

adhesion of H. pylori to gastric mucus and cells. A highmolecular-

weight, nondialyzable material from cranberry

juice was demonstrated to restrain the adhesion of twothirds

of the tested strains of H. pylori to immobilized

human gastric mucus and erythrocytes (54,55).

Preliminary results indicate that cranberry phenolics

may disrupt energy production and cause cell death (56).

In addition, cranberry phenolics may inhibit urease activity.

H. pylori releases the enzyme urease, which converts

urea into ammonia in the stomach. This neutralizes the

pH and protects H. pylori from stomach acid. Finally, the

H. pylori inhibiting factor may not be unique to cranberry

but common to all polyphenol-rich fruits (56,57). These in

vitro effects have been demonstrated in animal models,

with the administration of cranberry juice resulting in the

eradication of the pathogen; however, mechanisms and

specific cranberry constituents remain to be elucidated.

Antioxidant

Antioxidant capacity is not restricted to a particular class

of cranberry components but has been found in a wide

range of fractions (58). Polyphenols are reducing agents,

and together with others, such as vitamin C, they may protect

the body’s tissues against oxidative stress. The antioxidant

activity of the berry in vivo cannot be accounted for

on the basis of increased vitamin C alone (59). Crude cranberry

fruit extracts have significant antioxidant activity in

vitro (60). The total antioxidant activity of 100 g of cranberry

was estimated to be equivalent to that of 3120 mg

of vitamin C (12). Isolated polyphenolic compounds

from whole cranberries are comparable or superior to

that of vitamin E in their activity (18). Cranberry ranks

higher than apple, peach, lemon, pear, banana, orange,

grapefruit, pineapple, avocado, cantaloupe, melon, nectarine,

plum, and watermelon (13,61,62). However, cranberry

juices ranked lower in antioxidant potency using

a variety of antioxidant tests than many other leading

U.S. brands of ready-to-drink, polyphenol-rich beverages,

196 Klein

including pomegranate juice, red wine, Concord grape

juice, blueberry juice, black cherry juice, and Acai juice

(62). In comparing cranberry products to one another, it

appears that processing decreases the quality of antioxidants.

The quality is the result of changing the polyphenol

composition and is independent of the quantity of antioxidants

present (63).

The contribution of individual phenolics to total antioxidant

capacity is generally dependent on their structure

and content in the berry. The highest antioxidant activity

has been noted in peonidin-3-galactoside (21% of

antioxidant capacity). Quercetin-3-galactoside, cyanidin-

3-galactoside, and peonidin-3-arabinoside each contribute

about 10% to 11% (64). These four flavonoids have

the most potent antioxidant activities compared to 16

other isolated compounds, including plant sterols, other

flavonoids, derivatives of triterpenoids, and organic acids.

The isolated compounds may have additive and synergistic

effects (65). Animal model studies have shown wholebody

antioxidant potential at clinically relevant doses and

with dose-dependent responses (66,67).

Different methods of assessment of antioxidant capacity,

varying substrate systems, divergent ways of extraction,

length of storage, and differential concentrations

of active antioxidants confound the antioxidant activity–

chemical structure relationship. Given the diversity and

abundance of phenolic antioxidants in cranberry, considerable

potential exists for cranberry products to prevent

oxidative processes related to cardiovascular disease and

cancer at the cellular level and in vivo.

Atherosclerosis

 

Consumption of cranberry may decrease the risk of atherosclerosis

Possible mechanisms by which cranberry

may reduce risk include: (i) inhibition of lowdensity-

lipoprotein (LDL) oxidation (18,63), (ii) inhibition

of platelet aggregation and adhesion, (iii) inhibition of

the inflammatory response, (iv) induction of endotheliumdependent

vasodilation, and (v) increase of reverse cholesterol

transport and decrease of total and LDL cholesterol.

Data supporting these mechanisms are preliminary and

mostly from in vitro and animal model studies (69,70).

In vitro studies suggest that molecules like quercetin,

resveratrol, proanthocyanidin, anthocyanidin, hydroxycinnamic

acid, and acetylsalicylic acid may contribute

to an anti-inflammatory response. Human studies have

shown that cranberry increases total antioxidant capacity,

reduces plasma oxidized LDL (but not total LDL), and

reduces cell adhesion molecules (71,72). It has been

hypothesized that the potential effect of cranberry on

atherosclerosis may result from additive or synergistic effects

of multiple cranberry constituents due to various

mechanisms and not just the antioxidant effect alone. The

constituents contributing to the antioxidant effect were

previously addressed.

Cancer

The antioxidant capacity alone of cranberry constituents

may not account for the observed effects (61,73,74). A

soluble-free cranberry extract had the highest antiproliferative

activity and maximum calculated bioactivity index

for dietary cancer prevention compared to 10 other fruits

(12). Many of the cranberry compounds are likely contributors,

including the flavonols, anthocyanins, proanthocyanidins,

catechins, various phenolic acids, triterpenoids

(e.g., ursolic acid), and even stilbenes (e.g., resveratrol)

although these are present in lesser quantities than the

other constituents (65,70). Cranberry’s effect on tumor initiation,

growth, and metastases will depend largely on the

bioavailability of its phytochemicals to the various target

tissues.

Given the diversity of molecular structures and

bioactivity among the classes of phytochemicals in cranberry,

it is likely that they may fight cancer individually,

additively, or synergistically by several different mechanisms.

In vitro evidence in a variety of cell lines exists

for possible mechanisms, including (i) induction of apoptosis

in a variety of cancer cells, (ii) reduction of invasion

and metastasis by inhibition of matrix metalloproteinases,

(iii) inhibition of ornithine decarboxylase expression and

activity, (iv) inhibition of angiogenesis, (v) inhibition of

inflammatory processes, and (vi) inhibition of H. pylori,

a risk factor for gastric cancer (58,61,70,72,74–76). In

vivo carcinogenesis studies will need to be performed to

further confirm antitumor promotion activity and identify

individual components and mixtures responsible for

activity.

Safety Studies

No animal toxicology studies of any cranberry products

have been reported; however, two studies have reported

on safety in animal models. A mouse model study of the

effect of cranberry extract on cancer treatment reported

weight loss indicative of toxicity (77). A safety study of a

single oral dose of a proprietary multiberry supplement,

including cranberry (66), did not cause any mortality and

did not demonstrate any signs of gross toxicity, adverse

pharmacologic effects, or abnormal behavior in the treated

rats. Similarly acute dermal toxicity, primary skin irritation,

primary eye irritation via nonoral routes of administration

caused no toxicity or harm in animal models.

CLINICAL STUDIES

Efficacy

Urinary Tract Infection

The use of cranberry, particularly as a juice or juice cocktail,

to prevent or treat UTI is common. The accumulating

evidence from small, noncontrolled, and controlled clinical

trials suggests that the berry may relieve symptoms

associated with UTI and may reduce the need for antibiotics.

The Cochrane Library conducted separate reviews

of the fruit for the prevention (78) and treatment (79) of

UTI. For treatment, no trials meeting the inclusion criteria

were found; only a few uncontrolled trials were found. The

Cochrane Library concluded that there was no good quality

or reliable evidence of the effectiveness of cranberry

juice or other cranberry products for the treatment of UTI.

For both prevention and treatment, the review authors

concluded that more research was needed. For prevention,

10 studies were included in the review, of which only

four were of sufficient methodological quality to include

in the meta-analysis. Juice, juice cocktail, or concentrate

was investigated in seven studies and capsules or tablets

Cranberry

studied in four trials (one study investigated both juice

cocktail and tablets). Intervention duration ranged from

four weeks to one year and dosage was quite variable.

Several studies reported a high number of withdrawals,

and poor adherence to the intervention was also reported.

Side effects were common in all studies. The authors concluded

that cranberry products may decrease the number

of symptomatic UTIs over 12 months.

The National Institutes of Health (NIH) supported

four, large Phase 2 clinical studies to investigate the effect

of a research-grade, low-calorie cranberry juice cocktail on

the prevention of UTI in men and nonpregnant women at

high risk for UTI and in pregnant women. Subsequent to

the Cochrane reviews, results of the cranberry juice cocktail

study of asymptomatic bacteriuria in pregnancy have

been reported (80). Similar to other studies, a high number

of dropouts/withdrawals occurred and adherence to

the intervention protocol was poor which led to a protocol

change to reduce the dose of 240 mL (80 mg proanthocyanidin)

from three to two times a day. Despite the

limitation of the protocol change and problems with withdrawal,

adherence, and intervention tolerability, the data

suggest that cranberry juice cocktail may be protective of

asymptomatic bacteriuria and symptomatic UTIs in pregnancy.

Results from the other three NIH-supported trials

will be reported.

Many of the clinical study reports, with the exception

of the NIH-sponsored studies, suffer from major limitations.

Many trials have not been controlled or randomized,

and randomization procedures have not always been

described. Crossover designs used in some research may

not be appropriate for studies of UTI. Other limitations include

no blinding or failed blinding, lack of controlled diets

or dietary assessment, use of convenience samples, and

small numbers of subjects. Trials have been faulted for the

large number of withdrawals. Intention-to-treat analyses

were not often applied. Most studies have been conducted

in older or elderly patients. Very few have been conducted

in younger patients, with or without comorbidities, or in

men. Primary outcomes have differed from study to study

and have often included urinary pH, as well as rate of

bacteriuria, biofilm load, and urinary white and red blood

cell counts, rather than UTI. It is also not clear what the

optimum dosage or type of product is. There is limited

evidence of efficacy or safety for forms of cranberry product

other than juice or juice cocktail. Finally, the published

articles do not describe the quality and composition of the

products tested.

H. pylori Infection

A few randomized controlled studies of H. pylori infected

male and female adults and children have been undertaken

in China, Israel, and Chile with treatment outcomes

determined by the C urea breath test as the gold standard

to noninvasively detect active H. pylori infection (81–83).

Although study limitations exist and generalizability is

limited, results are encouraging and suggest that regular

consumption of cranberry juice as a complement or

alternative to standard triple therapy (a combination of

antibiotics and a proton pump inhibitor) may suppress

H. pylori infection. The studies suggest that females may

be more responsive and that the effect may not persist

when cranberry treatment is discontinued.

Adverse Effects

The U.S. Food and Drug Administration granted generally

recognized as safe (GRAS) status to cranberry foods and

beverages. This means that their safety is well established

when consumed in food amounts. The safety or harm of

dosages higher than food amounts cannot be confirmed

without further high quality clinical studies. The safety of

cranberry capsules, tablets, and concentrates, for example,

in which doses could reach pharmacologic levels, has not

been established.

The Cochrane reviews of UTI prevention and treatment

indicated that side effects were common in all cranberry

juice cocktail studies included in the reviews (78,79).

The reported side effects were primarily diarrhea or frequency

of bowel movements and other gastrointestinal

symptoms.

A review of the safety of cranberry consumption by

pregnant and lactating women indicated that there were

no clinical studies in the evidence-based medicine literature

of cranberry being either safe or contraindicated during

pregnancy or lactation (84). Subsequent to the review,

the first randomized, controlled trial of cranberry juice

cocktail for the prevention of bacteriuria in pregnancy

reported about 20% withdrawal due to gastrointestinal

upset, including nausea, vomiting, diarrhea, at a dose of

240 mL three times a day (80). When the dose was reduced

to two times a day, the juice cocktail was somewhat better

tolerated. There were no differences between the active

and placebo groups with regard to obstetric or neonatal

outcomes.

Observed Drug Interactions and Contraindications

There is insufficient reliable information available on cranberry

dietary supplements or juice cocktail to assess their

safety or their interaction with other dietary supplements,

foods, medications, or laboratory tests.

Because of its oxalate levels, cranberry may be a

causative factor in nephrolithiasis. The results of two small

studies of juice cocktail and tablets are equivocal, showing

differences in urine acidification, calcium and oxalate

excretion, and other promoters and inhibitors of stone formation

(85,86). A third study (87) was designed to specifically

assess the influence of diluted cranberry juice on

urinary biochemical and physicochemical risk factors for

calcium oxalate kidney stone formation. Three key urinary

risk factors were favorably altered: (i) oxalate (reported to

not be readily bioavailable from cranberry juice) excretion

decreased, (ii) phosphate excretion decreased, and (iii) citrate

(an inhibitor of stone formation) excretion increased.

There is one report of an infant hospitalized for cranberry

juice intoxication and acidosis (88).

Theoretically, the juice could interfere with the

copper-reduction glucose test because ascorbic acid (a

reducing agent) and hippuric acid have each been reported

to cause a false-positive reaction with the copperreduction

glucose determination in vitro. However, the results

of two small studies are equivocal and inconclusive

indicating that interference may be variable and dependent

on the type of reagent strip kit (89,90).

Limited studies have evaluated the drug interaction

potential of cranberry juice; no studies of cranberry supplements

are reported. The present hypothesis exerts that

constituents of cranberry and/or their metabolites may

198 Klein

interact with liver CYP isoenzymes or with intestinal and

renal drug transporters to alter the pharmacokinetics of

drugs. Factors that alter the metabolism of drugs play an

important role in dosing.

Only one study to date has examined the interaction

of cranberry and antibiotics commonly prescribed for recurrent

UTIs, amoxicillin and cefaclor (91). This study of

healthy women showed a modest delay in amoxicillin absorption

and a slight delay in cefaclor absorption, neither

delay being clinically significant. Their total absorption

and renal clearance were not affected.

Causal relationships cannot be proved by case reports;

however, they often help in identifying adverse

events and drug interactions. In 2003, the United Kingdom’s

Committee on Safety of Medicines alerted health

care professionals about the possibility of an interaction

between cranberry juice and warfarin, the most commonly

prescribed oral anticoagulation therapy (92). Five unsubstantiated

reported cases suggested an interaction (92). By

2004, the Committee had received 12 anecdotal case reports

of suspected interaction and concluded that there

was sufficient evidence of interaction, even though the

evidence was not credible (93).

It now appears that reports of enhanced antithrombotic

effects of warfarin associated with cranberry juice

administration may be a coincidence; however, there is inconsistency

among study findings. To address the effect of

cranberry on CYP2C9, evaluations have been conducted

in vitro and in vivo. In vitro studies have shown that

cranberry juice potentially inhibits CYP3A and CYP2C9

(94,95). On the other hand, a number of in vivo human

studies reported no alteration of warfarin pharmacokinetics

(95–99). In addition, studies of coadministration

of cranberry with other drugs primarily metabolized

by CYP2C9 (95,99) or metabolized by CYP3A (100) or

CYP1A2 (96) similarly show no pharmacokinetic change.

There does remain, nevertheless, potential drug interaction

liability with cranberry (101), because inconsistencies

among studies may be due to participant characteristics,

dosing, intervention duration, variability of cranberry test

materials, physiochemical effects of cranberry on drug absorption,

study design, and sample size.Worthy of further

investigation is the new evidence of genotype-dependent

interactions with warfarin (97).

Because information concerning the influence of

cranberry juice on the pharmacokinetics of CYP2C9 substrates

is limited, it may be premature to reach a definite

conclusion about the effect of cranberry juice on warfarin

pharmacokinetics. Nevertheless, patients who are coadministered

warfarin and especially large doses of cranberry

(102) should be monitored for the most appropriate

therapeutic range.

REGULATORY STATUS

In the United States, cranberry is classified as a food

when sold as juice, juice cocktail, and other conventional

forms. Cranberry products, such as encapsulated powders,

tablets, or tinctures, are regulated as “dietary supplements”

in the United States. In Canada, conventional

forms are sold as foods, whereas products promoting a

health claim are sold as “natural health products.”

CONCLUSIONS

There is a need for comprehensive chemical analyses of

all classes of compounds present in cranberry. Individual

structures and composition vary significantly among

cranberry products and its isolated constituents. Composition

varies by ripeness of the fruit, plant variety, growth

conditions, extraction method, and processing. This suggests

that bioactivities will also vary. However, quantitation

of complex polyphenols has been and continues to

be limited because of the lack of appropriate standardized

analytical methods. Consequently, the precise estimation

of cranberry constituent intake is hampered. Furthermore,

the bioavailability, metabolism, stability, purity, and composition

of cranberry products tested in clinical studies

have not been established or published. Therefore, the

ability to infer epidemiological relationships with health

and disease can be confounded.

Evidence for health benefit of cranberry is preliminary

and inconclusive. Current evidence from in vitro and

clinical studies has been conflicting. This could reflect differences

among sources of cranberry or its constituents,

form of product consumed, and level of intakes. In addition,

clinical studies performed to date have had many

methodological limitations and few have assessed safety.

Nevertheless, results of clinical studies are encouraging

for the relief of symptoms associated with and the prevention

of UTI.

The complex composition of cranberry creates problems

in extrapolation of research results on dietary intake

of individual constituents to intake of whole fruits or

extracts of whole fruits. Synergistic effects of the whole

may enhance the health benefits beyond what can be

achieved by the individual constituents. The complex mixture

of compounds could also protect against side effects.

More research on potential synergistic and protective

effects among the classes of compounds in cranberry

and with other food constituents and pharmaceuticals is

necessary.

For these reasons, it is important to understand the

composition of cranberry, determine the bioavailability

and metabolism of its constituents in isolation and as part

of the whole mixture, and rigorously examine the biologic

effects of cranberry on disease conditions in order to establish

its potential for being safe and providing health

benefit.