The Bioavailability of Dietary Flavonoids & Related Phenolic Compounds. Dietary phenolics. Feeding Studies. Stomach. Tissues. bile.

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1 The Bioavailability of Dietary Flavonoids & Related Phenolic Compounds Dietary phenolics Stomach Tissues Possible Routes for Consumed Dietary Phenolics in Humans bile General circulation Small intestine LIVER School of Medicine University of Glasgow Ileostomy bag Colon Kidney Faeces Urine Feeding Studies Absorption and Metabolism of Strawberry and Blackberry Anthocyanins 48 hr low polyphenol diet Lumen of small intestine Wall of small intestine (enterocyte) Portal vein Urine Fasted overnight H + H H Pelargonidin-3-glucoside LPH LPH CBG H H + Pelargonidin Supplement consumed H H + H Cyanidin-3-glucoside LPH LPH H H + H C Pelargonidin-3-glucuronide H H + H C Pelargonidin-3-glucuronide H H + H C Pelargonidin-3-glucuronide Blood and urine (ileal fluid) taken over 24 hr period To the large intestine (1% of intake)

2 Colonic Degradation of Anthocyanins Flavonol Glycosides H H H Quercetin-4'-glucoside H H H H H H Quercetin-3-rutinoside 2 g fried onions - 7 mmoles 3 ml tomato juice- 176 mmoles Excretion 3% Conc. nmoles/l Conc. nmoles/l Quercetin-4 -Glucoside Metabolites In Plasma Quercetin-3'-sulphate Quercetin-3-glucuronide A B Quercetin glucuronide sulphate Isorhamnetin-3-glucuronide Quercetin diglucuronide H H H Quercetin-4'-glucoside Flavonol Glycosides H H H H H H Quercetin-3-rutinoside 2 g fried onions - 7 mmoles 3 ml tomato juice- 176 mmoles

Fate of Rutin In The Large Intestine Quercetin-3-Rutinoside Metabolites In Plasma H Concentration (nmoles/l) 16 14 12 Quercetin-3-glucuronide 1 8 6 4 2

3-Methoxy-4-hydroxyphenylacetic acid Flavanones in ml of orange juice Flavanones in plasma after the ingestion of ml of orange juice 7 6 H H H H H Naringenin-7--rutinoside H H H

3 Fate of Rutin In The Large Intestine Quercetin-3-Rutinoside Metabolites In Plasma H Concentration (nmoles/l) Quercetin-3-glucuronide Isorhamnetin-3-glucuronide H H HC CH 3 Quercetin ring fission H H 3-Hydroxyphenylacetic acid HC H Rutin 3,4-Dihydroxyphenylacetic acid HC CH 3 3-Methoxy-4-hydroxyphenylacetic acid Flavanones in ml of orange juice Flavanones in plasma after the ingestion of ml of orange juice 7 6 H H H H H Naringenin-7--rutinoside H H H H H Hesperetin-7--rutinoside CH 3 nmol/l Hesperetin--glucuronides Urinary excretion Hesperetin metabolites - 4.4% of intake Naringenin metabolites % 12 mmoles 167 mmoles (Mullen et al. JAFC 11, , 28

CH 3 H H H H H hesperetin-7--rutinoside Urinary Excretion of Phenolic Acids after Drinking range Juice CH 3 H Colonic fate of range Juice Flavanones H -methylation hesperetin -demethylation H 2 HC

4 CH 3 H H H H H hesperetin-7--rutinoside Urinary Excretion of Phenolic Acids after Drinking range Juice CH 3 H Colonic fate of range Juice Flavanones H -methylation hesperetin -demethylation H 2 HC 3-methoxy-4-hydroxyphenyl hydracrylic acid -demethylation -demethylation CH 3 H2 H 2 -demethylation H HC 3-hydroxyphenyl hydracrylic acid conjugation H 2 C 3-hydroxyphenyl acetic acid Total (-24 h) Water 6.7 ± 1.8 a range juice 62 ± 18 b range juice with yoghurt 9.3 ± 4.4 a Data were expressed in mmole as mean values ± S.E. (n = ). H 2 CH 3 conjugation H 2 HC 4-hydroxy-3-methoxyphenylpropionic acid (dihydroferulic acid) HC NH 3-hydroxyhippuric acid Roowi et al. Mol Nutr Food Res, 3, S68-7, 29 Roowi et al. Mol Nutr Food Res, 3, S68-7, 29 Green Tea Flavan-3-ol Structures Flavan-3-ols in Choladi green tea H H (-)-Epicatechin H H H (+)-Catechin H H (+)-Gallocatechin H H H (-)-Epigallocatechin Green Tea Flavan-3-ols (µmoles/ ml) (+)-gallocatechin 36 (6%) ( )-epigallocatechin 7 (4%) (+)-catechin 9 (1%) ( )-epicatechin 8 (9%) ( )-epigallocatechin gallate 23 (3%) (+)-gallocatechin gallate 8 (1%) ( )-epicatechin gallate (8%) Total flavan-3-ols 648 (-)-Epicatechin gallate (-)-Epigallocatechin gallate (+)-Gallocatechin gallate

Flavan-3-ols and their metabolites in plasma after the ingestion of ml of Choladi green tea 14 3 12 1 8 6 4 2 EC sulfate 1 2 1 1 EC glucuronide 1 6 4 3 2 1 EGCg Recovery of Green Tea Flavan-3-ols in

(mmol) Parent flavan-3-ols 634 26 Flavan-3-ol metabolites - 232 Total 634 438 (69%) Stalmach et al.

4 --Methyl-(epi)gallocatechin--glucuronide 4.4 (Epi)gallocatechin--sulphates 2.6 4 --Methyl-(epi)gallocatechin--sulphates (9,1) 19.8 Total (epi)gallocatechin me tabolites 33.3 (11.

5 Flavan-3-ols and their metabolites in plasma after the ingestion of ml of Choladi green tea EC sulfate EC glucuronide EGCg Recovery of Green Tea Flavan-3-ols in -24 h Ileal Fluid Concentration (nm) Me-EC sulfate 1 Me-EGC sulfate EGC glucuronide 1 Me-EGC glucuronide ECg 1 1 Ingested (mmol) Recovered (mmol) Parent flavan-3-ols Flavan-3-ol metabolites Total (69%) Stalmach et al. Molecular Nutrition Food Research 4, S268-S277, 21 Flavan-3-ols in Urine after Ingestion of Choladi Green Tea Flavan-3-ol metabolites -24 h excretion (mmole) (Epi)gallocatechin--glucuronide Methyl-(epi)gallocatechin--glucuronide 4.4 (Epi)gallocatechin--sulphates Methyl-(epi)gallocatechin--sulphates (9,1) 19.8 Total (epi)gallocatechin me tabolites 33.3 (11.4%) (Epi)catechin--glucuronide 1. ±.3 (Epi)catechin--sulphates 6.7 ±.7 -Methyl-(epi)catechin--sulphates 1.9 ± 1.2 Total (epi)catechin meta bolite 19.1 (28.%) Total flavan-3-ol metabolites 2.4 (8.1%) metabolites excreted (umol) % Excretion of flavan-3-ol metabolites after ingestion of increasing doses of (epi)catechin after (epi)catechin and (epi)gallocatechin in Polyphenon E 3.% EGC dose (umol) 3.3% Auger et al. J Nutr 138, 13S-142S, 28 47% 6% 4% Stalmach et al. (29) MNFR 3, S44-3.

H H Procyanidin B 1 Lower unit HC CH 3 3-Methoxy-4-hydroxyphenylacetic acid H ( )-Epicatechin -(3',4'-Dihydroxyphenyl)-g-valerolactone HC 4-Hydroxyphenylacetic acid HC 4-Hydroxybenzoic acid Hippuric

3-Hydroxyphenylhydracrylic acid C Q A L s u l f a t e s H HC N Stalmach et al. Drug Met. Disp.

- - g l u c u r o n i d e H C C H 3 S - 3 F e r u l i c a c i d - 4 - - s u l f a t e H C D i h y d r o f e r u l i c a c i d - 4 - - s u l f a t e N H F e r u l o y l g l y c i n e C H 3 H C H 3 H H

6 H H Procyanidin B 1 Lower unit HC CH 3 3-Methoxy-4-hydroxyphenylacetic acid H ( )-Epicatechin -(3',4'-Dihydroxyphenyl)-g-valerolactone HC 4-Hydroxyphenylacetic acid HC 4-Hydroxybenzoic acid Hippuric acid Colonic degradation of procyanidins - I H 1-(3',4'-Dihydroxyphenyl)- 3-(2'',4'',6''-trihydroxyphenyl)propan-2-ol HC -(3',4'-Dihydroxyphenyl)valeric acid HC 3-(3'-Hydroxyphenyl)propionic acid HC 3-Hydroxyphenylhydracrylic acid C Q A L s u l f a t e s H HC N Stalmach et al. Drug Met. Disp. 37, , 29 H C H C H Bioavailability of Chlorogenic Acids in Humans After Drinking Coffee C H 3 H H H C H - - F e r u l o y l q u i n i c a c i d H H C H D i h y d r o f e r u l i c a c i d g l u c u r o n i d e H C C H 3 S - 3 F e r u l i c a c i d s u l f a t e H C D i h y d r o f e r u l i c a c i d s u l f a t e N H F e r u l o y l g l y c i n e C H 3 H C H 3 H H C C M T H C H 3 S - 3 G T C o A H H H C D i h y d r o f e r u l i c a c i d C o l o n H C C H 3 F e r u l i c a c i d H R A H - - C a f f e o y l q u i n i c a c i d H C D i h y d r o c a f f e i c a c i d g l u c u r o n i d e C H 3 H H C o l o n H C M T C M T H H C H C a f f e i c a c i d H C a f f e o y l q u i n i c a c i d l a c t o n e H H C M T E E E H G T H C H H H D i h y d r o c a f f e i c a c i d R A H H C H H C H C H C D i h y d r o ( i s o ) f e r u l i c a c i d H C H C H 3 I s o f e r u l i c a c i d S 3 - H S 3 - H D i h y d r o c a f f e i c a c i d s u l f a t e C o l o n C M T H H C C H 3 G T H C a f f e i c a c i d s u l f a t e G T H C H C H C H I s o f e r u l i c a c i d g l u c u r o n i d e S 3 - C H 3 C H 3 I s o f e r u l i c a c i d s u l f a t e S 3 - H C a f f e i c a c i d s u l f a t e C H 3 S m a l l i n t e s t i n e H H C H D i h y d r o ( i s o ) f e r u l i c a c i d g l u c u r o n i d e L a r g e i n t e s t i n e H H C H Pomegranates Nutritional Neuroscience, 8, Shukitt-Hale et al. 26. Effects of Concorde grape juice on cognitive and motor deficits in ageing. Nutrition 22, Shukitt-Hale et al. 29. Effects of blackberries on motor and cognitive function. Nutritional Neuroscience 12, Shukitt-Hale et al. 27. Beneficial effects of fruit extracts on neuronal function and behaviour in a rodent model of accelerated aging. Neurobiology and Aging 28,

Impact of phenolic catabolites on survival of human

µmol/l DMNQ British Journal of Nutrition (21), 14, 66 663.

hydrogen peroxide-induced oxidative stress and

percentage survival relative to survival of control cells

unpublished Impact of phenolic catabolites on glycation of

μmol/l 3 2 Increased viability (%) 2 1 1 Glycation

7 Impact of phenolic catabolites on survival of human neuroblastoma SK-N-MC cells incubated in 2. µmol/l DMNQ British Journal of Nutrition (21), 14, Biotransformed blueberry juice protects neurons from hydrogen peroxide-induced oxidative stress and mitogen-activated protein kinase pathway a Data expressed as percentage survival relative to survival of control cells treated only with 2. µmol/l of DMNQ. Del Rio et al. unpublished Impact of phenolic catabolites on glycation of BSA Impact of phenolic catabolites on survival of human neuroblastoma SK-N-MC cells incubated in 2. µmol/l DMNQ 6 1 μmol/l 4. μmol/l 3 2 Increased viability (%) Glycation inhibition (%) μmol/l Pom/Rasp Coffee Berries/Red wine 1

8 Impact of phenolic catabolites on glycation of BSA Thank You to The People Who Did All the Research Malaysia Glycation inhibition (%) μmol/l English Spain Venezuela Saudi Arabia Scottish/French Pom/Rasp Coffee Berries/ Red wine

Molecular Aspects of Medicine

Molecular Aspects of Medicine 31 (2010) 446 467 Contents lists available at ScienceDirect Molecular Aspects of Medicine journal homepage: www.elsevier.com/locate/mam Review Bioavailability of dietary flavonoids