Flavonoids and their contribution to health: a look at the scientific support Frank Hu, MD, PhD Professor of Nutrition and Epidemiology Harvard School of Public Health Professor of Medicine Harvard Medical School
Conflict of Interest Disclosures: None
Flavonoids polyphenolic compounds structure & nomenclature Share common basic structure Oxygenated heterocyclic middle ring (C) flanked by two aromatic rings (A,B) 6 sub-classes defined by variations in heterocyclic ring & functional groups Flavonol Flavanone Subtle differences in chemical structure affects biological properties HO O HO O HO O O Flavonols HO O O Flavones HO O + O Flavanones HO O Flavan-3-ols Anthocyanidins O Isoflavones Aedín Cassidy
Flavonoids Isoflavones Flavan-3-ols Flavanones Flavonols Flavones Anthocyanins Daidzein Monomers Polymers Hesperetin Quercetin Apigenin Cyanidin Genistein Catechin Procyanidins Naringenin Kaempferol Luteolin Pelargonidin Glycitein Epicatechin Malvidin <5 mg/d 157 mg/d 14 mg/d 13 mg/d <5 mg/d 3-1250 mg/d Total intake >1 g/day Average serving berries 400-500mg
HALF-LIFE Bioavailability Relative Bioavailability Relative Bioavailability Flavonoid sub-classes Flavonoid sub-classes Isoflavones Flavan-3-ols (Catechins) Flavanones Flavonols Anthocyanins Proanthocyanidins ~30% ~18.5% ~8.7% ~2.5% ~0.4% Flavones 6-8 hrs 2-4 hrs 5 hrs 4 hrs 2 hrs Proanthocyanidins limited evidence absorbed intact, Quantitative importance of their degradation products, microbial metabolites Highlights importance of developing biomarkers of intake Manach et al 2005
Molecular Mechanisms Beyond Antioxidant Effects Classic hydrogen donating antioxidant activity cannot explain bioactivity in vivo Activate endogenous defense systems stimulate expression phase II detoxification enzymes Modulate cell signaling pathways AP-1,MAPK, NADPH oxidase, metalloproteinases LDL HDL Flavan- 3-ols Insulin resistan ce Anti-inflammatory effects down regulate expression NF-kB and COX-2 Inhibit intestinal glucose transporters BP arterial stiffnes s endothelial function NO synthesis Biological relevance 50 um, plasma 1-5 um Parent compounds, in vivo effects mediated by metabolites Structure-Activity relationships, chemical structure alters bioactivity Differential effects different flavonoids Siow 2007, Kwon 2007, Schewe 2008 Wright et al 2010
Flavonoids and CHD/MI Mortality Ding et al., 2011 Nutrition & Metabolism
McCullough et al. AJCN 2012
Chocolate, cocoa & flavan-3-ols and risk factors for CVD Systematic review 42 acute / chronic studies 18wk duration Epicatechin dose > 50 mg/d > effect systolic & diastolic BP 50g chocolate 15g fat, 230 Kcal 10% energy intake Other sources of flavan-3-ols wine, tea, some fruit varieties Longer trials? Hooper L et al AJCN 2012
Taubert et al JAMA 2007 One square of Dark Chocolate SBP DBP
Randomized trials of cacao and CVD risk factors (Hooper et al AJCN 2008) Outcome Effect (95% CI) N studies P-value heterogeneity FMD chronic 1.45 (0.62, 2.28) 2 0.43 FMD acute 3.99 (2.86, 5.12) 6 0.10 Systolic BP -5.88 (-9.55, -2.21) 5 0.0003 Diastolic BP -3.30 (-5.77, -0.83) 4 0.009 11
Chocolate and Cardiovascular Disease Meta-analysis of 7 observational studies Chocolate consumption: chocolate bars, pieces, drinks, snacks (including confectionery, biscuits, desserts, nutritional supplements and candy bars) Buitrago-Lopez et al., 2011 British Medical Journal
Chocolate and Stroke Mink et al., 2007 Janszky et al., 2009 Buijsse et al., 2010 Larsson et al., 2011 Larsson et al., 2012 Larsson et al., 2012 Neurology
14 Blac Black tea and coronary heart disease (high vs. low) (Wang ZM AJCN 2011)
Randomized trials of black tea and CVD risk factors (Hooper et al AJCN 2008) Outcome Effect (95% CI) N studies FMD chronic 3.4% (1.9, 5.0) 1 -- FMD acute 1.7% (-0.2, 3.6) 3 0.0006 Systolic BP -0.03 (-2.8, 2.7) 4 0.99 Diastolic BP -0.57 (-2.0, 0.9) 4 0.96 LDL-cholesterol 0.05 (-0.15, 0.25) 3 0.76 HDL-cholesterol -0.01 (-0.07, 0.05) 4 0.81 P-value heterogeneity
AJCN 2012
Study Designs of Harvard Cohorts Nurses Health Study (121,701 women) 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996... 2010 Diet Diet Diet Diet Diet Diet Health Professionals Follow-up Study (51,529 men) 1986 1988 1990 1992 1994 1996 1998 2000... 2010 Diet Diet Diet Diet Diet Nurses Health Study II (116,686 young women) 1989 1991 1993 1995 1997 1999 2001... 2011 Diet Diet Diet Diet Every Two Years: Weight, smoking, physical activity, CVD risk factors, diseases. Every Four Years: Detailed dietary habits.
During 3.6 million person-years of follow-up, we documented 12,611 incident cases of diabetes. Higher intakes of anthocyanins were significantly associated with a lower risk of diabetes (pooled HR for the 3 cohorts from a comparison of extreme quintiles: 0.85; 95% CI: 0.80, 0.91; P-trend, 0.001) after multivariate adjustment for age, BMI, and lifestyle and dietary factors.
Fruit and Risk of Type 2 Diabetes In NHS I&II and HPFS Cantaloupe Strawberries Oranges Peaches, plums and apricots Grapefruit Bananas Apples and pears Prunes Grapes and raisins Blueberries Total fruits 0.6 0.7 0.8 0.9 1.0 1.1 Relative risk of type 2 diabetes Muraki et al., 2013
Blueberries (rich in anthocyanidins) and Health Approximately 2-4 servings a week (Average portion blueberries/blackcurrants exceed 500mg) Hypertension Diabetes Stroke Heart Disease 10% 23% 5% 34% Am J Clin Nutr, 2011 Am J Clin Nutr, 2012 Stroke, 2012 Circulation, 2013
SUMMARY-1 Large prospective cohort studies in combination with shorter-term trials of intermediary endpoints are critical in the absence of trials with disease endpoints Substantial observational evidence exists for a beneficial effects of intake of flavonoids and flavonoid-rich foods such as fruits, vegetables, chocolate on risk of chronic diseases More research is needed to clarify whether this reflects beneficial effects of flavonoids or other dietary constituents Small short-term trials have found potential cardiovascular benefits of cocoa flavan-3-ols on BP, endothelial function, and insulin resistance, but larger and longer term trials are needed
Challenges for epidemiologic studies Numerous factors influencing actual contents of polyphenols in plants: Sun exposure, ripeness of fruits, storage, food preparation, industrial processing, and etc. Measurement errors Food composition database Food frequency questionnaire Intake levels bioavailable dose Biomarker research Not subject to the sources of measurement errors for questionnaires EPI/NPAM 2013
Objective To evaluate urinary levels of selected polyphenol metabolites in relation to incident type 2 diabetes in two cohort studies: NHS 1 and 2 Lignan and whole grains: enterolactone and enterodiol Phenolic acid from coffee: caffeic acid and ferulic acid Flavonol from F/V: quercetin and isorhamnetin Flavanone: naringenin EPI/NPAM 2013
RRs of T2D according to quartiles of enterodiol and enterolactone: NHS 1 and 2 cohorts
RRs of T2D according to quartiles of quercetin: NHS 1 and 2 cohorts
Summary-2 Urinary concentrations of lignan and coffee metabolites are associated with lower risk of type 2 diabetes. Urinary concentrations of quercetin and isorhamnetin are associated with a lower diabetes risk in early follow-up period. These results are consistent with epidemiologic analysis of food intakes and disease risk Metabolites represent best integration of genetic and dietary influences and their interactions EPI/NPAM 2013
Conclusions Bioavailability & bioactivity of subclasses of flavonoids differs widely according to chemical structures Prospective cohort studies have provided some evidence on benefits flavonoids and flavonoid-rich foods Emerging data from biomarkers or metabolites of polyphenols have shown some promising results Small short-term RCTs have demonstrated benefits of cacao/flavan-3-ols on CVD risk factors Future directions: biomarkers of metabolites plus dietary assessment in large prospective studies; replications in various populations; better characterization of bioactive components; larger and longer term trials; independent and synergistic effects of multiple compounds
Acknowledgement Aedín Cassidy Eric Rimm Qi Sun Rob van Dam