Une connaissance fine des consommationsen flavonoïdes et de leur devenir dans l’organisme
est indispensable à l’évaluationde leurs effets sur la santé
Augustin SCALBERT
A L I M E N T A T I O N
A G R I C U L T U R E
E N V I R O N N E M E N T
Augustin SCALBERTUnité de Nutrition Humaine
Centre de recherche de Clermont-Ferrand
Flavonoids as antioxidantsFlavonoids as antioxidants
A generic propertyA generic property
OOH
OH O
OH
OH
OH
OOH
OH O
O
OH
OH
LH .L.
Stable radicals !
ControlCatechins
Propyl-gallate
Gallocatechins
Corn oil
+/- Polyphenols
50°C
2-16 days
Lipid hydroperoxides
Flavonoids as antioxidantsFlavonoids as antioxidants
A generic propertyA generic property
F2-isoprostane
Low
F2-isoprostane
Acute effects Longer term effects (1 wk)
Wiswedel et al., 2004, FRBM
� No consistent effect established on the long term
� Markers not yet recognized as independent risk factors for diseases
High
Hodgson et al., 2002, J. Nutr.
About 500 different polyphenols in foodsAbout 500 different polyphenols in foods
Lignans
OOH
OH
OH
CH2OH
O
OOH
OH
OH
OOH
OH O
O
OH
CH2OH
OH
OH
MeO
OMe
OOH
OH
OH O
CH2OH
OOH
OH
OH O
CH2OH
Flavonols
Isoflavones
StilbenesPhenolic acids
Flavonoids Lignans
OH
OH
O
O
OH
OOH
H
HH
OHOH
OH
OH
OOOH
OH
OH
CH2OH
Isoflavones
Catechins
Anthocyanins
Flavanones
Proanthocyanidins
Principales classes de flavonoïdesPrincipales classes de flavonoïdes
OH
O
O
OH
OH
OH
O
O
OH
OH
O
OOH
OH OH + OH
Flavonols Flavones Isoflavones
OH
O
O
OH
O
OH
OH
OH
O
OH
O
OH
O
OH
OH
OH
OH
OH
OH
OH
OH
O+
OH
OH
Flavanones
Flavanols Proanthocyanidines
Anthocyanes
Chemical structure and health outcomesChemical structure and health outcomes
O
OH
O
OH
� Closely related compounds may have different effects on life span
C. elegans
Zou et al., 2007, Mech. Ageing Dev.
Comparison of polyphenols in clinical trialsComparison of polyphenols in clinical trials
OOH
OH
OH
OH
12 healthy male subjects
200 mg polyphenols
Plasma 2 hrs later
OH
Plasma S-nitrosothiols
� Quercetin and epicatechin but not EGCG increase plasma NO
Loke et al., 2008, AJCN
OOH
OH
OH
OH
OH
OH O
Quercetin
Epicatechin
O
O
O
OH
OH
OH
OH
OH
OH
OH
OH
EGCG
Quercetin
Myricetin
GenisteinMorin
Epicatechin
CatechinRutin
Luteolin
Taxifolin
0 2 4
ABTS°+ reduction Cell growth inhibition
0 0,01 0,02
In vitroIn vitro screening for polyphenol bioactivityscreening for polyphenol bioactivity
Taxifolin
NaringeninApigenin
Chrysin
HesperetinKaempferol
Daidzein
GenistinBiochanin A
Hesperidin
FormononetinRice-Evans & Miller, 1996 Kuntz et al., 1999
� Relevance of such studies to compare health effects of polyphenols ?
� In vivo studies essential
Identification des métabolites actifs des polyphénols Identification des métabolites actifs des polyphénols
et de leurs cibles d’actionet de leurs cibles d’action
OOH
OH
HOOC
O O
� Flavonoids ingested
� Absorption in the gut
� Nature and concentration of the metabolites in target tissues
Food
Phytochem.metabolites Target
Health &diseases
OOH
CH2OH
O O
OOH
Une nouvelle base de données sur les Une nouvelle base de données sur les teneurs en polyphénols dans les alimentsteneurs en polyphénols dans les aliments
http://www.phenol-explorer.eu
- 506 phenolic compounds in 454 foods (300 flavonoids)- 1300 scientific publications analysed- 60,000 original content values collected and evaluated
Polyphenols in foods and beveragesPolyphenols in foods and beverages
0 100 200 300
Potato
Tomato
Lettuce
Onion
Apple
Phenolic acids
Flavonols
Catechins
Proanthocyanidins
Anthocyanins
Polyphenols (mg/100 g FW ou 100 ml)
Apple
Cherry
Whole grain wheat flour
Orange juice
Red wine
Coffee
Black tea
Chocolate
Anthocyanins
Flavanones
Others
1500
Source: www.phenol-explorer.eu
Polyphenol intakePolyphenol intake
Anthocyanins
Flavonols
Flavanones
SU.VI.MAX cohort
4,942 men & women
24-hr dietary records (x6)
Phenol-Explorer
OH
OH
O
O
OH
OOH
H
HH
OHOH
OH
OOH
H
HHOH
OH
O
O
OH
OOH
H
HH
OH
OH
OH
O
OOH
203 mg/day
271 mg/day
OOH
OH
OH
OH
OCH
3OH
OHOH
OOH
OH
O
OHO
+
36 mg/day
Hydroxybenzoicacids
Hydroxycinnamicacids
Catechins
Proanthocyanidins
1.8 g/day
OH
OH198 mg/day
OOH
OH
OH
OH
OH
OOH
OH
OH
OH
OH
32 mg/day 31 mg/day
� Flavonoid intake = 0.8 g/day
Non-alcoholizedVegetables
Alcoholizedbeverages
Nuts &beans
Dietary sources of polyphenolsDietary sources of polyphenols
6 %
Oils
Cereals
SU.VI.MAX cohort
4,942 men & women
24-hr dietary records (x6)
Phenol-Explorer
Non-alcoholizedbeverages
Fruits
Cocoa
49 %
11 %
9 %
8 % 6 % 6 %
1.8 g/day
Absorption et métabolisme des Absorption et métabolisme des polyphénolspolyphénols
Polyphénols
Métabolisme
par la microflore
du colon
Absorption au niveau
de l’intestin grêle
Métabolisme
par les tissus
(foie, intestin)
Large variations in flavonoid bioavailabilityLarge variations in flavonoid bioavailability
2 2
Pla
sm
a c
on
c.(
µm
ol /
L )
Pla
sm
a c
on
c.(
µm
ol /
L )
Single dose of 50 mg aglycone equivalentSingle dose of 50 mg aglycone equivalent
GenisteinGenistein (9)(9)
DaidzeinDaidzein (9)(9)
Querc Gluc.Querc Gluc. (7)(7)
RutinRutin (6)(6)
NaringinNaringin (6)(6)
(x)(x) = = Number of studiesNumber of studies0 0
1 1
00 22 44 66 88 1010 1212 1414 1616 1818
Time (hr)Time (hr)
Pla
sm
a c
on
c.(
µm
ol /
L )
Pla
sm
a c
on
c.(
µm
ol /
L )
AnthocyaninsAnthocyanins (6)(6)
EGCgEGCg (11)(11)
HesperidinHesperidin (5)(5)
NaringinNaringin (6)(6)
CatechinsCatechins (12)(12)
Manach et al. (2004) AJCN
Glycosylation influencesGlycosylation influencesthe gut absorption of flavonoidsthe gut absorption of flavonoids
16 healthy subjects
Orange juice
Flavanone concentrations in plasma (µM)
Orange juice
Orange juice+ hesperidinase
� The type of glycosylation is importantNielsen et al., 2006, J. Nutr.
O
O
OHOH O O
OH O
H
OH
O
OH
OH
OMe
OHOH
Me
O
OH
OHOH O O
OH O
H
OH
O
OH
Me
Hesperidinase
Flavonoid polymers are notFlavonoid polymers are notor poorly absorbed in the gutor poorly absorbed in the gut
Rats
Catechin or dimer B3, 0.1 % diet
HPLC-coularray
15co
nce
ntr
atio
n(µ
M)
OHOOH
OH
OH
OOH
OH
OH
OH
OH
0
5
10
3 hrs 9 hrs 3 hrs 9 hrs
Pla
sm
ati
c c
on
ce
ntr
atio
n
OOH
OH
OH
OH
OH
OH
Not detected
� Procyanidin dimer B3 is not absorbedDonovan et al., 2002, BJN
Flavonoids are largely metabolized in the tissuesFlavonoids are largely metabolized in the tissues
Entry
SmallIntestine
Bile
Living Rat
Mesentericblood
Entry
SmallIntestine
Bile
Living Rat
Mesentericblood
OOH
OH
OH
OH
OSO3-
OOH
OH
OH
OH
O OOH
OH
CH2OH
COOH
Catechin metabolites (µM)
Mesenteric plasma Bile
- Free 0 0
- Glucuronide 0.7 0.2
- Glucuronide/sulfate 0 0.8
Donovan et al., 2001, J. Nutr.
ExitExit
OHOH
Biological activity of flavonoid conjugatesBiological activity of flavonoid conjugates
Rat aortic rings
Ach (induces vasorelaxation)
DETCA (inhibits SOD)
+ Quercetin or
Quercetin metabolites
OOH
OH
OOH
OH
O
OH COOH
� Lower vasorelaxation with quercetin metabolites
Lodi F. et al., 2009, Atherosclerosis
OOH
OH O
OH
OH
OH
O OH
OH O
O
CH2OH
Flavonoids are metabolized in the colonFlavonoids are metabolized in the colon
Human colonic microflora 14C-Proanthocyanidin polymers
Autoradiography
GC-MS
OH
CH2
CH2
CH2
CH2
COOH
OH
OH
OOH
OH
OH
OH
OH
OOH
OH
OH
CH2
CH2
COOH
OH
CH2
COOH
CH2
CH2
COOH
CH2
OH
COOH
CH2
CH2
COOH
OOH
OH
OH
OH
OH
OH
OH
OOH
OH
OH
OH
OH
OOH
OH
OH
OH
OH
OOH
OH
OH
OH
OH
Aromatic acids
� Proanthocyanidins are degraded by the microflora
0 4824
Time (hrs)
Déprez et al., 2000, J. Nutr.
Flavonoids and Flavonoids and in vitro in vitro studiesstudies
0,1 1 10 100 1000(Ludwig et al., 2004)
(Choi et al., 2004)(Hernandez-Montes et al., 2006)
(Reiterer et al., 2004)
(Fuchs et al., 2005)(Kim et al., 2005)
(Chao et al., 2005)(Mnjoyan et al., 2003)
(Pal et al., 2003)
Active flavonoid concentrations (µM)
Endothelial cells
Aortic smoothmuscle cells
Nutritional(Pal et al., 2003)(Gouedard et al., 2004)
(Martinez-Florez et al., 2005)
(Mullen et al., 2004)(Sarkar et al., 2004)
(Richard et al., 2005)(Kim et al., 2005)
(Moreno et al., 2003)(Mackenzie et al., 2003)
(Yang et al., 1998)
(Biswas et al., 2005)(Abate et al., 2005)
(Kim et al., 2004)
Hepatocytes
Immune cells
Lung epithelial cellsFibroblastsβ-cells
Nutritionalpolyphenol
concentrations
� Few studies so far published on flavonoid metabolites
� Tested at very high concentrations
Difficult today to predicthealth effects from in vitro studies
Flavonoids Flavonoids –– Intake and bioavailabilityIntake and bioavailability
� Total flavonoid intake 0.8 mg/day
� About 300 different flavonoids in the diet
� Most largely consumed flavonoids
– Anthocyanins– Anthocyanins
– Catechins
– Proanthocyanidins
� Absorption in the gut highly variable
– Glycosides
– Polymers
� Biological properties of metabolites should be studied
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