Ilja C. W. Arts

Polyphenols and disease risk in epidemiologic studies

Plant polyphenols, a large group of natural antioxidants, are serious candidates in explanations of the protective effects of vegetables and fruits against cancer and cardiovascular diseases. Epidemiologic studies are useful for evaluation of the human health effects of long-term exposure to physiologic concentrations of polyphenols, but reliable data on polyphenol contents of foods are still scarce. The aim of this review is to summarize available epidemiologic data on the health effects of polyphenols, focusing on the flavonoid subclasses of flavonols, flavones, and catechins and on lignans. Data obtained to date suggest beneficial effects of both flavonoids and lignans on cardiovascular diseases but not on cancer, with the possible exception of lung cancer. There is a need for more research on stroke and lung diseases such as asthma and chronic obstructive pulmonary disease. Most studies to date have included only flavonols and flavones. With data becoming available for other polyphenols, these compounds should be included in future studies. Careful design of prospective studies is important to offset some of the major drawbacks of epidemiologic studies, including residual confounding (by smoking and other dietary factors) and exposure assessment.

Flavonols, flavones and flavanols – nature, occurrence and dietary burden

Total flavonol and flavone contents of foods have been determined with validated state-of-the-art methods. Quercetin dominates, and flavonol levels found in vegetables and fruits are below 10 mg kg−1. However, high concentrations are found in onions (300 mg kg−1), kale (450 mg kg−1), broccoli (100 mg kg−1), beans (50 mg kg−1), apples (50 mg kg−1), blackcurrants (40 mg kg−1), and tea (30 mg l−1). The dietary intake of flavonols varies 10-fold between countries (6–60 mg day−1). Flavones are of minor importance in the diet. Tea, wine and fruits are the most important sources of flavanols, but there are gaps in our knowledge on flavanol levels of many foods. The absorption of dietary quercetin glycosides in humans ranges from 20 to 50%. The sugar moiety is an important determinant of the bioavailability of flavonols. The presence of a glucose moiety significantly enhances absorption. The extent of absorption of flavanols in humans seems similar to that of flavonols but has been little studied. Flavonols and flavanols are extensively metabolised, as only 1–2% of them are excreted with an intact flavonoid backbone. Hepatic biotransformations include glucuronidation and sulphatation of the phenolic hydroxyls and O-methylation of catechol groups. Bacteria of the colon cleave the C-ring of the flavonoid nucleus to phenolic acids which are subsequently absorbed. Apart from conjugates, virtually no metabolites have been characterised in humans. Absorption of flavanols is rather fast, with times to reach peak values between 0.5 and 4 h. Flavanols are rapidly excreted, with elimination half-lives of 1–6 h. Quercetin glycosides show rapid to slow absorption; peak values are reached between  < 0.5 and 9 h. The type of glycoside determines the rate of absorption. Excretion of quercetin glycosides is slow: elimination half-lives are 24 h, independent of the type of glycoside. Analytical data for flavanols in foods are needed. Tea, as an important dietary source, has to be studied. Research on the bioavailability of flavonols and flavanols has to be expanded. Attention is needed for the identification and quantification of their metabolites in body fluids. © 2000 Society of Chemical Industry

Lignan contents of Dutch plant foods: a database including lariciresinol, pinoresinol, secoisolariciresinol and matairesinol

Enterolignans (enterodiol and enterolactone) can potentially reduce the risk of certain cancers and cardiovascular diseases. Enterolignans are formed by the intestinal microflora after the consumption of plant lignans. Until recently, only secoisolariciresinol and matairesinol were considered enterolignan precursors, but now several new precursors have been identified, of which lariciresinol and pinoresinol have a high degree of conversion. Quantitative data on the contents in foods of these new enterolignan precursors are not available. Thus, the aim of this study was to compile a lignan database including all four major enterolignan precursors. Liquid chromatography-tandem mass spectrometry was used to quantify lariciresinol, pinoresinol, secoisolariciresinol and matairesinol in eighty-three solid foods and twenty-six beverages commonly consumed in The Netherlands. The richest source of lignans was flaxseed (301,129 microg/100 g), which contained mainly secoisolariciresinol. Also, lignan concentrations in sesame seeds (29,331 microg/100 g, mainly pinoresinol and lariciresinol) were relatively high. For grain products, which are known to be important sources of lignan, lignan concentrations ranged from 7 to 764 microg/100 g. However, many vegetables and fruits had similar concentrations, because of the contribution of lariciresinol and pinoresinol. Brassica vegetables contained unexpectedly high levels of lignans (185-2321 microg/100 g), mainly pinoresinol and lariciresinol. Lignan levels in beverages varied from 0 (cola) to 91 microg/100 ml (red wine). Only four of the 109 foods did not contain a measurable amount of lignans, and in most cases the amount of lariciresinol and pinoresinol was larger than that of secoisolariciresinol and matairesinol. Thus, available databases largely underestimate the amount of enterolignan precursors in foods.

Chocolate as a source of tea flavonoids

The antioxidant catechin content of chocolate is four times that of tea. Chocolate contributed 20% of the catechin intake in a representative sample of the Dutch population, and tea contributes 55%. Epidemiological assessments of health effects of tea should include other foods that are sources of catechins.

Dietary catechins and cancer incidence among postmenopausal women: the Iowa Women's Health Study (United States)

Objective: Catechins are bioactive flavonoids present in tea, fruits, and vegetables. Previous epidemiological studies regarding tea and cancer risk were inconclusive, possibly because catechins are also present in other plant foods. We investigated whether a high intake of catechins are associated with cancer incidence among postmenopausal women. Methods: A cohort of 34,651 postmenopausal cancer-free women aged 55–69 years were followed from 1986 to 1998. At baseline, data on diet, medical history, and lifestyle were collected. Incident cancers were obtained through linkage with a cancer registry. Cox proportional hazards analysis was used to estimate risk ratios. Results: After adjustment for potential confounders, catechin intake was inversely associated with rectal cancer incidence only (risk ratios from lowest to highest quartile: 1.00, 0.93, 0.73, and 0.55; p for trend 0.02). Non-significant inverse trends were found for cancer of the upper digestive tract, pancreas, and for hematopoietic cancers. Catechins derived primarily from fruits, (+)-catechin and (−)-epicatechin, tended to be inversely associated with upper digestive tract cancer, whereas catechins derived from tea were inversely associated with rectal cancer. Conclusions: Among several cancers studied, our data suggest that catechin intake may protect against rectal cancer. The distinct effects found for catechins derived from solid foods (fruits) and beverages (tea) may be due to differences in bioavailability or metabolism of the catechins, or to their interactions with other dietary components.

Dietary catechins in relation to coronary heart disease death among postmenopausal women

Catechins, one of the major groups of flavonoids, are bioactive compounds present in a variety of plant foods and beverages. Experimental data suggest that they might prevent chronic diseases in humans. We studied whether the intake of catechins was inversely associated with the risk of coronary heart disease death in a prospective study of postmenopausal women from Iowa. Between 1986 and 1998, 767 of 34,492 participants initially free of cardiovascular diseases died from coronary heart disease. There was a strong inverse association between the intake of (+)-catechin and (−)-epicatechin and coronary heart disease death, which was somewhat attenuated after multivariate adjustment (risk ratios from lowest to highest quintile: 1.00, 0.95, 0.97, 0.77, 0.76). This inverse association was most pronounced in women at low risk of coronary heart disease (non-smokers, free of diabetes mellitus and cardiovascular diseases). A high intake of “gallates,” catechins typical of tea, was not associated with coronary heart disease death. Of the major catechin sources, apples and wine were inversely associated with coronary heart disease death. Our data suggest that preventive effects might be limited to certain types of catechins, or that these are indicators of other dietary components or a healthy lifestyle in general.

SIRT1 stimulation by polyphenols is affected by their stability and metabolism

Silent information regulator two ortholog 1 (SIRT1) is the human ortholog of the yeast sir2 protein; one of the most important regulators of lifespan extension by caloric restriction in several organisms. Dietary polyphenols, abundant in vegetables, fruits, cereals, wine and tea, were reported to stimulate the deacetylase activity of recombinant SIRT1 protein and could therefore be potential regulators of aging associated processes. However, inconsistent data between effects of polyphenols on the recombinant SIRT1 and on in vivo SIRT1, led us to investigate the influence of (1) stability of polyphenols under experimental conditions and (2) metabolism of polyphenols in human HT29 cells, on stimulation of SIRT1. With an improved SIRT1 deacetylation assay we found three new polyphenolic stimulators. Epigallocatechin galate (EGCg, 1.76-fold), epicatechin galate (ECg, 1.85-fold) and myricetin (3.19-fold) stimulated SIRT1 under stabilizing conditions, whereas without stabilization, these polyphenols strongly inhibited SIRT1, probably due to H2O2 formation. Using metabolically active HT29 cells we were able to show that quercetin (a stimulator of recombinant SIRT1) could not stimulate intracellular SIRT1. The major quercetin metabolite in humans, quercetin 3-O-glucuronide, slightly inhibited the recombinant SIRT1 activity which explains the lack of stimulatory action of quercetin in HT29 cells. This study shows that the stimulation of SIRT1 is strongly affected by polyphenol stability and metabolism, therefore extrapolation of in vitro SIRT1 stimulation results to physiological effects should be done with caution.

Catechin intake and associated dietary and lifestyle factors in a representative sample of Dutch men and women.

Objective: To study the intake of catechins in the Dutch population and to assess the relation between catechin intake and other dietary factors. Catechins, dietary components that belong to the flavonoid family, potentially protect against chronic diseases such as cancer and cardiovascular diseases. Catechins are the major components of tea, but they are present in many other plant foods as well.Design: Data were used from a nationwide dietary survey carried out in 1998 among a representative sample of 6200 Dutch men and women aged 1–97 y. Dietary data were collected using a 2 day dietary record method.Results: The average daily catechin intake was 50 mg (s.d. 56 mg/day). Catechin intake increased with age, and the intake was higher in women (60 mg/day) than in men (40 mg/day). Tea was the main catechin source in all age groups, whereas chocolate was second in children, and apples and pears were second in adults and elderly. Catechin intake was lower in smokers than in non-smokers, and increased with socio-economic status. A high intake was associated with a high intake of fiber (r=0.20), vitamin C (r=0.17) and beta-carotene (r=0.10).Conclusions: Catechins are quantitatively important bioactive components of the daily diet, which should be taken into account when studying the relation between diet and chronic diseases. Catechin intake is only moderately associated with the intake of other nutrients, but much stronger with certain health behaviours such as smoking.Sponsorship: Commission of the European Communities Agriculture and Fisheries (FAIR) specific RTD Programme CT95 0653.European Journal of Clinical Nutrition (2001) 55, 76–81

Dietary catechins and epithelial cancer incidence: the Zutphen elderly study

The flavonoids, a group of more than 4,000 polyphenolic antioxidants, are potential cancer preventive components of fruits and vegetables. Catechins, one of the 6 major groups of flavonoids, are present in high concentrations in tea as well. Our objective was to evaluate the association between intake of catechins and incidence of epithelial cancers with data from the Zutphen Elderly Study, a prospective cohort study among 728 men aged 65–84 years in 1985. The average catechin intake at baseline was 72 mg/day (range, 0–355 mg/day). After 10 years of follow‐up, 96 incident epithelial cancers were recorded, including 42 cases of lung cancer. After multivariate adjustment, catechin intake was not associated with epithelial cancer (risk ratio [RR] from lowest to highest tertile: 1.00, 0.75, 0.94; p for trend: 0.82), or lung cancer (RR from lowest to highest tertile: 1.00, 0.72, 0.92; p for trend: 0.80). Catechins not from tea were borderline significantly inversely associated with lung cancer incidence (RR and 95% confidence interval [CI] for a 7.5‐mg increase in intake: 0.66, 0.42–1.05), whereas catechins from tea were not. Catechins from apple, the major source of non‐tea catechins, were also related to lung cancer incidence (RR and 95% CI for a 7.5‐mg catechin increase: 0.67, 0.38–1.17). Because tea, the major catechin source in this population, was not associated with cancer risk, it seems unlikely that catechins are responsible for the observed inverse trend between non‐tea catechins and lung cancer incidence. However, differences in bioavailability of the various catechins may play a role; effects on individual cancer sites cannot be excluded and merit further investigation.

Plasma Enterolignans Are Associated with Lower Colorectal Adenoma Risk

Lignans are biphenolic compounds that occur in foods of plant origin such as whole grains, seeds, fruits and vegetables, and beverages, such as coffee and tea. Plant lignans are converted by intestinal bacteria into the enterolignans, enterodiol and enterolactone. Enterolignans possess several biological activities, whereby they may influence carcinogenesis. We studied the associations between plasma enterolignans and the risk of colorectal adenomas in a Dutch case-control study. Colorectal adenomas are considered to be precursors of colorectal cancer. Cases (n = 532) with at least one histologically confirmed colorectal adenoma and controls (n = 503) with no history of any type of adenoma were included. Plasma enterodiol and enterolactone concentrations were measured by liquid chromatography with tandem mass spectrometry. Associations were stronger for incident than for prevalent cases. When only incident cases (n = 262) were included, high compared to low plasma concentrations of enterodiol were associated with a reduction in colorectal adenoma risk after adjustment for confounding variables. Enterodiol odds ratios (95% confidence intervals) were 1.00, 0.69 (0.42-1.13), 0.60 (0.37-0.99), and 0.53 (0.32-0.88) with a significant trend (P = 0.01) through the quartiles. Although enterolactone plasma concentrations were 10-fold higher, enterolactones reduction in risk was not statistically significant (P for trend = 0.09). Use of oral antibiotic therapy could decrease the plasma concentrations of enterolactone. Exclusion of antibiotic users resulted in similar odds ratios for both enterolignans, but the association for enterolactone became somewhat stronger (P = 0.05 versus P = 0.09). We observed a substantial reduction in colorectal adenoma risk among subjects with high plasma concentrations of enterolignans, in particular, enterodiol. These findings could be important in the prevention of colorectal adenomas. (Cancer Epidemiol Biomarkers Prev 2006;15(6):1132–6)