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Polyphenols and disease risk in epidemiologic studies1–4 ABSTRACT
In addition to their antioxidant properties, polyphenols show Plant polyphenols, a large group of natural antioxidants, are serious several interesting effects in animal models and in vitro systems; candidates in explanations of the protective effects of vegetables and they trap and scavenge free radicals, regulate nitric oxide, de- fruits against cancer and cardiovascular diseases. Epidemiologic crease leukocyte immobilization, induce apoptosis, inhibit cell studies are useful for evaluation of the human health effects of proliferation and angiogenesis, and exhibit phytoestrogenic ac- long-term exposure to physiologic concentrations of polyphenols, tivity (3– 6). These effects may contribute to their potentially but reliable data on polyphenol contents of foods are still scarce. The protective role in cancer and CVDs. The question remains of aim of this review is to summarize available epidemiologic data on whether these data are relevant for human disease outcomes, the health effects of polyphenols, focusing on the flavonoid sub- where exposure to polyphenols is chronic and at relatively low classes of flavonols, flavones, and catechins and on lignans. Data concentrations, depending on bioavailability and metabolism.
obtained to date suggest beneficial effects of both flavonoids and An important phenomenon is that, after absorption, polyphenols lignans on cardiovascular diseases but not on cancer, with the pos- are subject to phase II metabolism, yielding methoxylated, glu- sible exception of lung cancer. There is a need for more research on curonidated, and sulfated compounds (7). This may greatly in- stroke and lung diseases such as asthma and chronic obstructive fluence their bioactivity, but only a few studies have examined pulmonary disease. Most studies to date have included only fla- this to date. In addition, bacteria present in the human colon vonols and flavones. With data becoming available for other poly- metabolize polyphenols. The major polyphenol metabolites are a phenols, these compounds should be included in future studies.
variety of phenolic acids such as homovanillic acid (8). As a Careful design of prospective studies is important to offset some of consequence, body tissues are exposed to high concentrations of the major drawbacks of epidemiologic studies, including residual confounding (by smoking and other dietary factors) and exposure Although no information on causality can be obtained, epide- Am J Clin Nutr 2005;81(suppl):317S–25S.
miologic studies are useful for evaluation of the human health effects of long-term exposure to physiologic concentrations of KEY WORDS
polyphenols. Reliable data on polyphenol contents of foods are vonoids, flavonols, catechins, lignans, antioxidants, phytoestrogens, needed for studies of the potential role of dietary polyphenols in cancer and CVD prevention. Comprehensive data are availableonly for the flavonoid subclasses of flavonols, flavones, andcatechins, but data on other polyphenols, such as lignans, are INTRODUCTION
forthcoming. In this article, we provide an overview of epidemi- Epidemiologic studies suggest a protective effect of vegeta- ologic studies on the health effects of flavonols, flavones, cat- bles and fruits against cancer and cardiovascular diseases echins, and lignans conducted to date.
(CVDs) (1, 2). Various hypotheses have been suggested to ex-plain these beneficial effects of increased consumption of veg-etables and fruits. An attractive hypothesis is that vegetables and FLAVONOIDS
fruits contain compounds that have protective effects, indepen- dent of those of known nutrients and micronutrients. Plant poly-phenols, a large group of natural antioxidants ubiquitous in a diet Of the 6 major classes of flavonoids, comprehensive data on their high in vegetables and fruits, certainly are serious candidates. All contents in foods are available only for the flavonols (quercetin, plant phenols are derived from the common intermediate phe-nylalanine, or its close precursor shikimic acid, through the 1 From RIKILT-Institute of Food Safety, Wageningen University and shikimic acid pathway in plants. They can be divided into at least Research Centre, Wageningen, The Netherlands.
10 different classes on the basis of their general chemical struc- Presented at the 1st International Conference on Polyphenols and Health, tures, with the common characteristic being at least one aromatic held in Vichy, France, November 18 –21, 2004.
3 Supported by grant QLK1-CT-1999-00505 from the European Commu- ring structure with one or more hydroxyl groups. A large variety nity, Framework V Programme (POLYBIND), by the Dutch Ministry of of plant (poly)phenols exist, including cinnamic acids, benzoic Agriculture, Nature Management, and Fisheries, and by the Netherlands acids, flavonoids including proanthocyanidins, stilbenes, cou- Organisation for Health Research and Development (grant 014-12-014).
marins, lignans, and lignins. Within each family of plant phenols, 4 Address correspondence to ICW Arts, RIKILT-Institute of Food Safety, many compounds may be present. For example, Π6000 different Wageningen University and Research Centre, PO Box 230, 6700 AE, flavonoids occurring in plants have been described.
Wageningen, The Netherlands. E-mail: ilja.arts@wur.nl.
Am J Clin Nutr 2005;81(suppl):317S–25S. Printed in USA. 2005 American Society for Clinical Nutrition TABLE 1
Prospective studies of flavonoid intake and risk of CVDs1
MI, myocardial infarction; —, no data provided.
2 Flavonols: quercetin, kaempferol, myricetin; flavones: apigenin, luteolin; flavanones: hesperetin, naringenin, eriodictyol; catechins: (ѿ)-catechin, (ѿ)-gallocatechin, (Ҁ)-epicatechin, (Ҁ)-epigallocatechin, (Ҁ)-epicatechin gallate, (Ҁ)-epigallocatechin gallate.
3 Mean, median, or category cutoff value.
4 Death, unless indicated otherwise.
5 95% CI in parentheses.
6 Quartiles were constructed for men and women separately, but RR is provided for sexes combined only.
kaempferol, and myricetin), flavones (apigenin and luteolin), and Finnish Mobile Clinic Health Examination Survey (significant catechins [(ѿ)-catechin, (ѿ)-gallocatechin, (Ҁ)-epicatechin, (Ҁ)- among men only) (22), the Iowa Women’s Health Study, a cohort epigallocatechin, (Ҁ)-epicatechin gallate, and (Ҁ)-epigallocatechin study of 34 500 women in the United States (20), the Alpha- gallate]. The flavonoid data used in most epidemiologic studies Tocopherol, Beta-Carotene Cancer Prevention Study among were based on analyses conducted in the Netherlands (9 –12) but 25 000 male smokers (19), the Dutch Zutphen Elderly Study for were supplemented in some studies with data for additional food catechins (18), and the Rotterdam Study in the Netherlands, a items. Recently, data became available for flavanones in Finnish cohort study of 4800 men and women (16). In a large cohort study foods (hesperetin, naringenin, and eriodictyol) (13). Except for of 35 000 male US health professionals, a suggestion of a reduc- one study from the United Kingdom (14), all epidemiologic tion in coronary mortality rates with high flavonol intake was studies of flavonoids are from the Netherlands, Finland, or the found only among men with a previous history of CAD [relative risk (RR): 0.63; 95% CI: 0.33, 1.20] (23). In contrast, a trend forincreased CAD mortality rates (P for trend ҃ 0.12) was found in the Caerphilly Study, a cohort study of 1900 Welsh men (14). It To date, 12 cohort studies on flavonoid intake and the risk of was suggested that the English habit of adding milk to tea (the coronary artery disease (CAD) and 5 cohort studies on the risk of major source of flavonols for this cohort) could inhibit the ab- stroke have been published (Table 1). Seven of these prospective
sorption of flavonols, thus explaining the lack of protection of tea studies found protective effects of flavonols and flavones or of flavonols against CAD. Proteins bind phenols efficiently and catechins with respect to fatal or nonfatal CAD, and reductions therefore might inhibit absorption from the gastrointestinal tract of mortality risk were up to 65%. These studies were as follows: when consumed together with flavonoids. However, it was the Zutphen Elderly Study, with a small cohort of 805 men in the shown that the absorption of flavonols was not impaired with the Netherlands after 5 and 10 y of follow-up monitoring (21, 24), the addition of milk (27). Residual confounding by lifestyle factors might have affected evaluation of the results of this study among Enterolignans are found in biological fluids of humans and ani- mals (6, 39). It was shown, that in addition to the well-known Two of 5 studies of flavonoid intake and stroke risk found an enterolignan precursors secoisolariciresinol and matairesinol, inverse association, ie, the Zutphen Elderly Study and the Finn- several other plant lignans were converted into enterolactone and ish Mobile Clinic Health Examination Survey (Table 1). In the enterodiol, although with varying degrees of efficiency (40). The Zutphen Elderly Study, a protective effect was observed for health effects of lignans were evaluated in epidemiologic studies flavonols and flavones (26) but not for catechins (18).
that used both the intake of secoisolariciresinol and matairesinoland plasma or urinary concentrations of enterolactone and en- terodiol as exposure estimates. The calculated intake of secoiso- Associations between the intake of flavonoids and the inci- lariciresinol and matairesinol was based on published food com- dences of a variety of cancers have been studied in 7 prospective position tables (41– 43), of which that provided by De Kleijn et cohort studies (Table 2) and 4 case-control studies. Significant
al (41) is the most comprehensive. Of 8 published studies on associations were observed only for lung cancer and colorectal enterolignan concentrations and the risk of CVD or cancer, only cancer. Two Finnish studies with relatively low intakes of fla- 2 measured enterodiol in addition to enterolactone. Enterolac- vonols and flavones, ie, the Finnish Mobile Clinic Health Exam- tone is usually measured with a time-resolved fluoroimmunoas- ination Survey (30) and the Alpha-Tocopherol, Beta-Carotene say, which is not available for enterodiol (44).
Cancer Prevention Study (32), found inverse associations withlung cancer risk (RR: 0.53; 95% CI: 0.29, 0.97; and RR: 0.56; 95% CI: 0.45, 0.69, respectively). In contrast, a borderline pos- Two publications (45, 46) from one Finnish cohort study in itive association was found for colorectal cancer risk in the which plasma enterolactone concentrations were studied in re- Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study lation to CVD risk reported significant inverse associations (Ta-
(RR: 1.70; 95% CI: 1.00, 2.70; P for trend ҃ 0.10). For catechins, ble 3). In the Finnish Kuopio Heart Disease Risk Factor Study,
an inverse association was reported for rectal cancer (RR: 0.55; a 65% lower risk of incident CAD was observed (46). With 2 95% CI: 0.32, 0.95; P for trend ҃ 0.02), but not for colon cancer, additional years of follow-up monitoring, the risk of CAD death among postmenopausal women in the United States. No evi- was of the same order of magnitude (RR: 0.44) and similar, dence for an effect of flavonoid intake was found for the inci- although results were only borderline significant for total CVD dence of any epithelial cancer or cancer of the stomach, urinary deaths (RR: 0.55) (45). The association between serum en- tract, prostate, or breast. None of the case-control studies of terolactone concentrations and plasma F -isoprostane concen- prostate (34), lung (35), testicular (36), and ovarian (37) cancer trations (a biomarker of in vivo lipid peroxidation) was studied cross-sectionally in a subset of 100 male participants in the An-tioxidant Supplementation in Atherosclerosis Prevention Study Other chronic diseases
(47). With higher enterolactone concentrations, F -isoprostane Because of their antioxidant and antiinflammatory properties, concentrations were significantly lower (P ҃ 0.02).
flavonoids may also beneficially influence other chronic dis- No studies on lignan intake and CVD risk have been published eases involving oxidative stress or inflammation, such as rheu- to date, but 2 cross-sectional studies related lignan intake to CVD matoid arthritis and chronic obstructive pulmonary disease risk factors. Of several risk factors studied among postmeno- (COPD). Knekt et al (13) studied the associations between the pausal US women, only the waist-hip ratio (difference between intake of flavonols, flavones, and flavanones and the incidences extreme quartiles: Ҁ0.017; 95% CI: Ҁ0.030, Ҁ0.002; P for trend of rheumatoid arthritis, type 2 diabetes mellitus, cataracts, and ҃ 0.03) and the metabolic syndrome score, a summary score of asthma among a cohort of ȁ10 000 male and female participants several risk factors (difference between extreme quartiles: in the Finnish Mobile Clinic Health Examination Survey (Table Ҁ0.55; 95% CI: Ҁ0.82, Ҁ0.28; P for trend ҃ 0.0001), were 2). A significant inverse association was observed only for associated with intake of secoisolariciresinol and matairesinol asthma (RR: 0.65; 95% CI: 0.47, 0.90; P for trend ҃ 0.04). This (48). Aortic stiffness, assessed with pulse-wave velocity mea- finding supported an earlier cross-sectional study, in which in- surements of the aorta, was borderline significantly inversely take of flavonoids was beneficially associated with pulmonary associated with lignan intake among postmenopausal Dutch function and symptoms of COPD. Pulmonary function (mea- women (49). The regression coefficient for those with a high sured as forced expiratory volume in 1 s) was better among intake of lignans was Ҁ0.41 (95% CI: Ҁ0.93, 0.11; P for trend ҃ subjects in the highest quintile, compared with the lowest quin- 0.06), compared with those with a low intake. The protective tile, of intake of flavonols, flavones, and catechins (44 mL; 95% effect was most pronounced and significant among women with CI: 18, 69 mL). Catechin intake alone was most strongly asso- ciated with the forced expiratory volume in 1 s (130 mL; 95% CI:101, 159 mL) and with all 3 symptoms of COPD [cough odds ratio (OR): 0.72; 95% CI: 0.58, 0.90; phlegm OR: 0.60; 95% CI:0.47, 0.75; breathlessness OR: 0.69; 95% CI: 0.52, 0.90] (38).
To date, 3 prospective, nested, case-control studies and 3 case- control studies have studied plasma or urinary lignan concentra-
tions and cancer risk (Table 4); all except one investigated breast
cancer incidence. The 2 prospective, nested, case-control studieson breast cancer risk, among Dutch postmenopausal women (54) and among female participants in 3 cohorts in northern Sweden Plant lignans can be converted by human intestinal bacteria (53), found no relationship with plasma or urinary enterolactone into the so-called enterolignans, ie, enterolactone and enterodiol.
concentrations. In contrast, all 3 case-control studies found an TABLE 2
Prospective studies of flavonoid intake and risk of incident cancer and other chronic diseases1
Flavonols, flavones, M Œ 26.9 vs  4.3,6 Goldbohm et al, 1998 (33) Netherlands 3799 MF Flavonols, flavones, M Œ 26.9 vs  4.3,6 Goldbohm et al, 1998 (33) Netherlands 3306 MF Flavonols, flavones, M Œ 26.9 vs  4.3,6 Goldbohm et al, 1998 (33) Netherlands 3726 MF Flavonols, flavones, M Œ 26.9 vs  4.3,6 Goldbohm et al, 1998 (33) Netherlands 2203 F TABLE 2
Continued
1 —, no data provided.
2 Flavonols: quercetin, kaempferol, myricetin; flavones: apigenin, luteolin; flavanones: hesperetin, naringenin, eriodictyol; catechins: (ѿ)-catechin, (ѿ)-gallocatechin, (Ҁ)-epicatechin, (Ҁ)-epigallocatechin, (Ҁ)-epicatechin gallate, (Ҁ)-epigallocatechin gallate.
3 Mean, median, or category cutoff value.
4 Design in parentheses if other than prospective cohort.
5 95% CI in parentheses.
6 Quartiles were constructed for men and women separately, but RR is provided for sexes combined only.
inverse association between lignan concentrations and breast breast cancer among premenopausal women (RR: 0.49) but not cancer risk (52, 55, 56). When a subset of postmenopausal postmenopausal women (RR: 0.72) in western New York State women only was included in the analysis of the Shanghai Breast (58). In contrast, breast cancer risk was borderline significantly Cancer Study, the inverse association was no longer significant elevated with a high intake of secoisolariciresinol and mataires- and the RR increased from 0.40 (95% CI: 0.24, 0.64) to 0.50 inol among a large group of women participating in the multi- (95% CI: 0.23, 1.10) (51). In all of these case-control studies, ethnic Bay Area Breast Cancer Study (RR: 1.3) (59) and of plasma or urine was collected after diagnosis and sometimes secoisolariciresinol only in the prospective California Teachers even after initiation of treatment of the disease, which might have Study (RR: 1.4) (57). In the latter study, the association was influenced lignan concentrations through changes in the diet as a substantially attenuated to a RR of 1.2 (95% CI: 0.9, 1.6) after result of disease or through other mechanisms. The only study on adjustment for wine consumption. This led the authors to con- prostate cancer risk conducted to date found no association with clude that the increased risk with secoisolariciresinol was attrib- plasma enterolactone concentrations among a large cohort of utable to confounding by alcohol consumption.
male residents of Finland, Norway, and Sweden (50).
Significant or borderline significant protective associations Intake of the lignans secoisolariciresinol and matairesinol was were also reported for endometrial cancer (60), ovarian cancer studied in relation to the risk of several cancers in 1 prospective (37), and thyroid cancer (61) among female participants. No cohort and 3 case-control studies, all from the United Stated associations between lignan intake and incident prostate (34) or (Table 4). A significant inverse association was observed for TABLE 3
Prospective studies of serum lignans and risk of CVDs1
1 ENL, enterolactone.
2 Design in parentheses if other than prospective cohort.
3 Death, unless indicated otherwise.
4 95% CI interval in parentheses.
TABLE 4
Prospective and case-control studies on plasma or urinary lignan concentrations or dietary lignan intake and incident cancer1
1 ENL, enterolactone; END, enterodiol; SECO, secoisolariciresinol; MAT, matairesinol; —, no data provided.
2 Mean, median, or category cutoff value; plasma values in nmol/L, urine values as indicated, intake levels in mg/d.
3 Follow-up time in parentheses.
4 95% CI in parentheses.
5 ENL and END production from foods determined by in vitro fermentation with human fecal microflora.
DISCUSSION
0.44) for 3 studies from continental Europe, and 0.95 (95% CI: In the past decade, several well-designed, prospective, cohort 0.84, 1.08) for 8 studies from the United States. Explanations for studies in which the health effects of flavonoids were studied this phenomenon, which also seems to occur for flavonoids, have been published. The data regarding CVD suggest protective include differing associations with a healthy lifestyle and publi- effects of high intakes of flavonols and flavones and possibly of cation bias. However, no satisfactory explanation has been pro- catechins. However, only a few studies are available for cat- vided, and research into these differences seems worthwhile.
echins and for stroke; given the results obtained to date, these Attempts to distinguish the effects of flavonols and flavones deserve more study. A meta-analysis of tea consumption in re- from those of catechins were undertaken with data from the lation to CAD and stroke, including all studies published up to Zutphen Elderly Study (18, 29) and demonstrate one of the major October 2000, was conducted by Peters et al (62). Most studies limitations of component-based epidemiologic studies. Each included in the current review were also included in that meta- food contains a large number of different compounds, some analysis, because they provided data not only for tea, which is a known and quantified, some less well characterized, and some major flavonoid source, but also for flavonoids. Peters et al (62) unknown or unmeasurable. Many compounds tend to be present found evidence for publication bias, particularly with respect to in the same foods or families of foods. The intake of catechins, for stroke, and therefore urged caution in interpreting the results for example, was positively correlated with the intake of fruits and this endpoint. Publication bias might have occurred for flavonoid vegetables and their constituents, eg, vitamin C, vitamin E, caro- epidemiologic studies as well. Another striking finding is that tenoids, folate, and fiber. For the intake of vitamin C, ␤-carotene, studies of CAD or myocardial infarction conducted in continen- and fiber, correlations in several European populations on the tal Europe reported strong inverse associations, whereas studies order of 0.40-0.70 were reported (63). When the correlation is too conducted elsewhere did not. Summarized RRs for drinking 3 high, it is impossible to ascertain independent effects of dietary cups per day compared with no tea were 1.62 (95% CI: 1.15, components, because of multicollinearity. This was the case for 2.30) for 2 studies from the United Kingdom, 0.27 (95% CI: 0.16, flavonols and catechins in the Zutphen Elderly Study. Tea supplied 87% of this population’s intake of catechins and 61% of should be conducted on the lignan-cancer association before any the intake of flavonols and flavones (24). To circumvent multi- collinearity problems but still distinguish the effects of catechins The quality of dietary intake assessment and of food compo- from those of flavonols, subgroups were defined, ie, tea, cat- sition tables is crucial in the component-based epidemiologic echins from sources other than tea, and flavonols from sources approach. Imprecision of exposure measurement is an important other than tea. Independent effects on CAD mortality rates were limitation of these studies. If valid biomarkers are available, then borderline significant for tea (P ҃ 0.06) and catechins from other these may replace questionnaire-based assessment of exposure; sources than tea (P ҃ 0.11). For correct interpretation of results for most compounds, however, no biomarkers that reflect long- of dietary component-based epidemiologic studies, adjustment term exposure are available. No studies using biomarkers of for other dietary factors (both nutrient and nonnutrient) is of flavonoid intake have been conducted to date. In contrast, several studies have used plasma or urinary enterolactone concentrations Data are less convincing for cancer. Of several cancers stud- as biomarkers of lignan exposure. A major drawback of most of ied, protective effects have been reported only for lung cancer in those studies was that enterodiol, the other enterolignan pro- relation to flavonol and flavone intake. Together with data from duced by the colonic microflora, was not measured. It was re- one cohort study and one cross-sectional study suggesting ben- cently shown that not only secoisolariciresinol and matairesinol eficial effects on asthma and lung function, these data suggest a but also several other plant lignans, including pinoresinol and role for flavonoids in lung health that merits additional investi- lariciresinol, are converted into enterolignans (71). We deter- gation. For colorectal cancer, data are inconsistent, with 1 posi- mined the concentrations of these 2 additional lignans in plant tive, 1 inverse, and 4 null associations. Residual confounding by foods and found that their intake is severalfold higher than that of smoking is the most serious drawback of the flavonoid studies secoisolariciresinol and matairesinol (IEJ Milder, ICW Arts, and published to date. Unhealthy (or healthy) behaviors tend to clus- PCH Hollman, unpublished results, 2004). These compounds ter. Smoking, which is the single most important risk factor for should be included in future evaluations of the health effects ofdietary lignans.
many cancers and an important determinant of CVDs, is associ- Epidemiologic studies can be useful tools to study the health ated with higher intakes of energy, alcohol, and fat, lower intakes effects of polyphenols. Data obtained to date suggest of a bene- of fruits and vegetables, lower socioeconomic status, and phys- ficial effect on CVD but not on cancer, with the possible excep- ical inactivity (64 – 66). Previous studies showed that consump- tion of lung cancer. There is a need for more research on stroke tion of important sources of flavonoids, such as tea in the Neth- and lung diseases such as asthma and COPD. Most studies have erlands (67) and in Japan (68) and wine in Denmark (69), is included flavonols and flavones only. With data becoming avail- associated with healthy dietary patterns. Residual confounding able for other polyphenols, these should be included in future occurs if confounders such as smoking are insufficiently ac- studies. Careful design of prospective studies is important to counted for in statistical analyses. Insufficient control for con- offset some of the major drawbacks of epidemiologic studies, founders can occur as a result of misclassification of the con- including residual confounding (by smoking and other dietary founding factors, and control thus depends on the quality and amount of detail with which the confounders are measured. Inparticular, if the confounding is strong, as is usually the case forsmoking, then misclassification of the confounder can yield spu- REFERENCES
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