prenylated isoflavonoids from plants as selective estrogen receptor modulators

Prenylated isoflavonoids from plants as s

M

se a

ds a

ith

ha

ost

foo

isoflavonoids show agonistic activity towards both hERa and hERb, the extent of which is modulated

514

ospadias in male offspring in

compounds was first encoun-

disease, when sheep became

ntaining it.17 Infertility was also

ere fed on a diet rich in soya

isoflavones. No subsequent associations of soya intake and

Dynamic Article LinksC

Structural features of isoflavonoids

Subclassification of isoflavonoids

The family of phenylbenzopyrans can be divided into 4 classes

based on the position of the aromatic B-ring on the benzopyran

moiety (or chromene moiety, i.e. rings A and C): 2-phenyl-

benzopyrans (often referred to as flavonoids), 3-phenyl-

benzopyrans (isoflavonoids), 4-phenylbenzopyrans (neoflavonoids)

and miscellaneous flavonoids (without the pyran C-ring, such as

chalcones and phenyl benzofurans). The first steps in phenyl-

benzopyran biosynthesis lead to the formation of chalcones, and

subsequently flavanones.1 Isoflavonoids are derived from flava-

nones by consecutive C3 hydrogen abstraction of the benzopyran

moiety, migration of the aromatic B-ring from the C2 to C3, and

C2 hydroxylation.23,24 This so-called aryl rearrangement performed

by isoflavanone synthase (2HIS) and the subsequent water loss by

isoflavanone dehydratase (2HID) lead to the formation of the

isoflavones genistein or daidzein, depending on the presence of the

5-hydroxyl group (Fig. 1).1,25 Isoflavonoids lacking the 5-hydroxyl

group (as in daidzein) are also called 5-deoxyisoflavonoids. All

isoflavonoids are thought to originate from daidzein and genistein

which are, therefore, considered key elements in the structural

diversification of isoflavonoids.26

Isoflavonoids are subdivided into 13 subclasses based on the

level of oxidation of the C-ring and the occurrence of additional

heterocyclic rings.25 The biosynthetic relationships of the

isoflavonoid subclasses are illustrated in Fig. 1. Six subclasses

have a typical 3-ring carbon frame with a 6-membered C-ring

(isoflavones, isoflavanones, isoflav-3-enes, isoflavans, isoflavan-

4-ols, and 3-phenyl coumarins). In addition, five subclasses

(pterocarpans, coumestans, rotenoids, coumaronochromones

and coumaronochromenes) are characterised by an additional

D-ring. It is thought that the isoflavones and pterocarpans are

the largest two subclasses comprising 40% and 20% of allmolecular species of isoflavonoids, respectively.27 Based on their

proposed biosynthesis pathway, a-methyldeoxybenzoins and 2-

phenyl-benzofurans are included within the class of iso-

flavonoids. However, based on their deviating C-ring structures,

a five-membered C-ring (2-phenyl benzofurans) and open C-ring

(a-methyldeoxybenzoins), they might also be categorised differ-

ently, i.e. belonging to the class of miscellaneous flavonoids.

Prenylation of isoflavonoids

Prenylation refers to substitution with a C5-isoprenoid (or prenyl)

group. In a broader sense, prenylation also refers to the substitu-

tion with other isoprenoid groups, including C10-isoprenoid (ger-

anyl) or C15-isoprenoid (farnesyl).28 In this review, the term prenyl

will refer to the C5-isoprenoid group. Prenylation increases the

lipophilicity of molecules, which results in an increased affinity to

biological membranes and an improved interaction with target

tic r

sio

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. View Article OnlineFig. 1 Biosynthesis of isoflavones from (2S)-flavanones, and biosynthe

Dewick et al. and Veitch et al.2,25 Dashed arrows indicate proposed conver

one reaction is involved. It should be noted that the flavanone precursor is

flavanone. The unsubstituted isoflavonoids do not occur naturally.This journal is The Royal Society of Chemistry 2012elationships between the various isoflavonoid subclasses, adapted from

ns, awaiting further proof. A double arrow head indicates that more than

droxylated molecule, either 5,7,40-trihydroxy flavanone or 7,40-dihydroxyFood Funct., 2012, 3, 810827 | 811

proteins.29 Furthermore, it has been suggested that prenylation

plays a crucial role in modulating bioactivity.29,30

Isoflavonoids are predominantly C-prenylated, although

O-prenylation of isoflavonoids occurs as well.31 The prenyl chain

generally refers to the 3,3-dimethyl allyl (3,3-DMA) substituent,

which is considered to be the predominant type of prenylation.28

The group of prenyl chains also includes variations of the 3,3-

DMA structure (Fig. 2). A prenyl chain may undergo enzymic

cyclisation (presumably a prenyl cyclase) with an ortho-phenolic

hydroxyl group leading to 6-membered pyran derivatives.32 The

common 2,2-dimethylchromeno substituent is often termed

a pyran ring (Fig. 2). Cyclisation of a prenyl chain may also result

in the 5-membered furan derivatives (Fig. 2). C-prenylation at

positions 6 and/or 8, as well as 30 or 50, for the six isoflavonoidsubclasses having a typical 3-ring carbon frame appear to be

generally preferred.33 For the 5 subclasses having an additional

D-ring, the positions are similar, but numbered differently,

depending on the isoflavonoid (see Fig. 1). For example, in

pterocarpans and coumestans positions 2, 4, 8, and 10 corre-

spond to positions 6, 8, 50, and 30 in isoflavones, respectively.Most prenylated isoflavonoids are considered to be inducible

metabolites,28,33 which are often produced as part of the plants

defensive strategy upon biotic stress (e.g. pathogenic microorgan-

isms)34 or abiotic stress (e.g. chemical elicitors).35 For example,

prenylated pterocarpans called glyceollins are well-known to

accumulate in stress-induced soya bean sprouts.3643 Sometimes

these inducible metabolites are referred to as phytoalexins. They

increasingly gain scientific interest due to their bioactivities, such as

anti-cancer activity, and their potential to enhance the nutritional

value of crops.22

Other decorations of isoflavonoids

The class of isoflavonoids is characterised by large structural

variations ranging from various degrees of oxidation of the C-

ring to substitutions of the carbon skeleton through hydroxyl-

ation, alk(en)ylation (including O-methylation and prenylation),

glycosylation and sulfation.1,3,4,33,44 Isoflavonoids mainly occur

as O-glycosides in which the sugar moiety is connected to the

carbon skeleton via a hydroxyl group with the formation of

a glycosidic (acetal) bond.45 Occasionally, the glycosyl residue is

linked to the aromatic ring by a CC bond, an example of which

is the isoflavone C-glycoside puerarin.46 Glycosylation often

involves glucose, but also substituted sugars, such as acetyl-

glucosides and malonyl-glucosides, which are the predominant

isoflavonoid conjugates found in soya.45,47

Dietary sources of isoflavonoids

Non-prenylated isoflavonoids

Isoflavonoids occur mainly in the family of the Leguminosae,

which comprises more than 19 000 species divided over an

noi0 0-d

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. View Article OnlineFig. 2 A representative overview of common prenyl-substituents in flavo

Sometimes pyran/furan rings are numbered differently. For example, 60 0,6812 | Food Funct., 2012, 3, 810827ds, adapted from Barron et al.28 17,8-(2,2-dimethylpyrano) or pyran ring.

imethylpyrano[7,8:20 0,30 0] equals 7,8-(2,2-dimethylchromeno).This journal is The Royal Society of Chemistry 2012

isoflavonoids. Some subclasses are formed from isoflavones

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. View Article Onlineupon exposure to intestinal microbiota, i.e. isoflavans, iso-

flavenes, isoflavanones, and a-methyl deoxybenzoins, as

described later on.

Prenylated isoflavonoids

Data on the occurrence of prenylated isoflavonoids in foods and

their subsequent dietary intake is rather limited. A rich source of

prenylated isoflavonoids is licorice. Licorice roots fromGlycyrrhiza

glabra are known to contain large amounts of glabridin, a preny-

lated isoflavan, with up to 3.5 mg g1 in licorice.57,58 Rough esti-

mates regarding glabridin intake might be based on the average

intake of licorice products such as licorice candy. The intake of

licorice root in the US is estimated at 369 mg per person per day.59

With a glabridin content of 0.35% w/w, this results in a daily intake

of up to 1.3 mg glabridin per day. The consumption of licorice is

estimated to be 20 higher in the Netherlands.60 Besides glabridin,licorice roots contain also a number of other prenylated iso-

flavonoids, i.e. glabrene, glabrone, hispaglabridin A and B, which

have so far not been quantified accurately.61

Many prenylated isoflavonoids have been isolated from

sprouts of leguminous seeds.62 Sprouting of seeds under biotic or

abiotic stress offers a potentially interesting method to induce

larger amounts of prenylated isoflavonoids that might be

employed as e.g. nutraceuticals.22 Soya beans have been exten-

sively investigated in this respect.3643,63 Interestingly, it has been

shown that this induction of prenylated isoflavonoids is

amenable to up-scaling, as malting (similar to that employed to

barley prior to brewing) of soya beans effectively led to the

accumulation of 2.2 mg g1 DW of these compounds.43 Lupin(Lupinus ssp.) has an isoflavone content comparable to that ofestimated 727 genera.1 The Leguminosae is an economically

important family of flowering plants, as it harbours many edible

legumes such as soybeans (Glycine max), beans (Phaseolus ssp.),

peas (Pisum sativum), chickpeas (Cicer arietinum), alfalfa

(Medicago sativa), peanut (Arachis hypogaea) and licorice

(Glycyrrhiza ssp.). Most reviews on the isoflavonoid content of

dietary sources are limited to the amounts of isoflavones, the

predominant subclass in foods.10,4850

Soya-based foods, in particular, are the largest contributor to

dietary isoflavone intake. The levels of isoflavones, mainly rep-

resented by daidzein and genistein and their respective conju-

gates, in soya-based foods range from less than 0.1 mg g1 up to

2 mg g1.12,48,49,51 The levels of coumestans are 100 to 1000 times

lower compared to isoflavones,51,52 although some studies report

levels up to 0.3 mg g1 48 and 6 mg g1 53 in soya and clover

sprouts (Trifolium ssp.), respectively. The mean dietary intake of

isoflavones through the consumption of soya and soya-based

products in Asian countries is 2540 mg day1, with a maximum

intake of up to 120 mg day1.54,55 With several mg day1, the

dietary isoflavone intake in Western countries is considerably

lower.49,52,56 The increasing use of botanical supplements con-

taining e.g. isoflavone-rich soy extracts compensates for this

difference in part of theWestern population.49 The dietary intake

of coumestrol, the main dietary representative of the coumestans,

is estimated to be 0.3 mg day1 in Korea, mainly through soya-

products. To the best of our knowledge, there is currently no

information available on dietary intake of other subclasses ofThis journal is The Royal Society of Chemistry 2012soya beans, and can be processed in a similar fashion as soya.64

Lupin grown under stress is known to contain both non-preny-

lated and prenylated isoflavones; the content of the latter can

amount to 1.1 mg g1 DW.6568 The occurrence of prenylated

isoflavonoids in non-stressed, field-grown soya plants suggests

that prenylated isoflavonoids can also be formed under normal

conditions.6971

Bioavailability of isoflavonoids


Isoflavones appear to have the highest bioavailability among the

phenylbenzopyrans.50 Isoflavones have been the prime focus of

research concerning isoflavonoid bioavailability (Table 1). In

soya and soya-based foods, isoflavones are predominantly

present in their glycosidic forms, which are poorly absorbed in

the intestinal tract.72 Hydrolysis of the glycosidic bond is,

therefore, considered essential for absorption of isoflavones.

Upon ingestion, isoflavone glycosides are hydrolysed by

b-glycosidases of the brush border cells in the small intestine and

by the b-glycosidases of the intestinal microbiota, such as

Lactobacillus spp., Bacteroides spp. and Bifidobacterium spp.73,74

Once absorbed, isoflavones are converted by phase II metabo-

lism to their respective glucuronide, sulphate and O-methyl

conjugates in the gut mucosa and inner tissues.73Non-conjugated

isoflavones are virtually absent in plasma.72,75

Apart from the glucuronide and sulphate conjugates of iso-

flavones, such as daidzein and genistein, other isoflavone

metabolites have also been detected in human plasma and urine

samples.72,76,77 These metabolites are formed upon microbial

degradation in the GI-tract and represent different isoflavonoid

subclasses: equol (isoflavan), dehydroequol (isoflavene), dihy-

drodaidzein and dihydrogenistein (isoflavanones), O-desmethy-

langolensin and 6-hydroxy-O-desmethylangolensin (a-methyl-

deoxybenzoins).45,7680 Pharmacokinetic studies showed that

equol is more bioavailable than the isoflavones daidzein and

genistein.81,82 Apart from equol, there have been no studies

specifically investigating the bioavailability of other metabolites

found in plasma.

Due to its presence in various soya foods, the bioavailability of

coumestrol (coumestan) has been studied. A recent study

demonstrated the presence of small amounts of coumestrol in

human urine samples, indicating that it is absorbed.83 The low

concentration of coumestrol in the urine samples might be

explained by its low intake due to its low levels and limited

occurrence in food.83 No direct comparisons have been made

with respect to the bioavailability of isoflavones versus coume-

stans. Moreover, there are no studies investigating the bioavail-

ability of other non-prenylated isoflavonoids.


There are only a few studies on the bioavailability of prenylated

isoflavonoids (Table 1). In two human studies, the human plasma

concentration of glabridin was determined upon ingestion of

single and multi-dosage of 3 to 12 mg glabridin in the form of

a standardised licorice extract (1 g glabridin per 100 g

sample).84,85 Maximum plasma levels of up to 2.5 ng mL1 were

reached 4 h after ingestion of the highest dose. Glabridin wasFood Funct., 2012, 3, 810827 | 813

Table1

Summary

ofdietary

occurrence,bioavailability,microbialandliver

metabolitesofvarious(prenylated)representatives

fortheisoflavonoid

subclasses.a

Prenyl(#

prenyl)

Rem

arks

Dietary

occurrence

Bioavailability

Microbialmetabolites

Phase

IandIImetabolites

Ref.

Isoflavones

Unprenylated

No

Main

representatives:

daidzein,genistein,

glycitein,biochanin

A,

form

ononetin,andtheir

conjugates

G.max

Deglucosylationpriorto

absorptionisessential

Dem

ethylationofO-M

eisoflavones,equol,dehydroequol,

diH

daidzein,diH

genistein,

O-desMeangolensin,60 -O

HO-desMeangolensin

Hydroxylationsmainlyat

6,8and30 p

ositionsGlcA,

Meandsulfateconjugates

12,44,4851,

7282,9297,

104,105

L.albus

T.pratense

(#2.0mgg1)

Isoflavonemetabolites

detectedin

blood

andurine

Prenylated

Chainb(1)

AringandBring

prenylatedisoflavones,

e.g.luteone,wighteone

G.max

n.d.

n.d.

n.d.

42,65,66

L.albus

(#1.1mgg1)

Chainb(2)

Lupalbigenin,

L.albus

n.d.

n.d.

n.d.

65

20 -O

Hlupalbigenin

Chainb(2)

IsoangustoneA

G.uralensis

Parentcompoundandits

metabolitesdetectedin

blood,

urineandfeces

n.d.

GlcAconjugates

(mono,di),aldehyde

conjugates,hydroxylations

(mono-tri)

87

Chainb(1)

LicoisoflavoneA

GlcAconjugatesdetectedin

blood,urineandfeces

GlcAconjugates

(mono,di)

87

Pyranc(1)

LicoisoflavoneB

Pyranc(1)

Sem

ilicoisoflavoneB

Isoflavanones

Unprenylated

No

DiH

daidzein,diH

genistein,diH

glycitein

anddiH

biochanin

Amicrobialmetabolites

ofdaidzein,genistein,

glycitein

andbiochanin

A,resp.

n.a.

n.d.

n.d.

n.d.

45,76,79,

97,162

Prenylated

Chainb(1)

Kievitone

P.vulgaris

(#1.2mgg1)

n.d.

n.d.

n.d.

157

Isoflavans

Unprenylated

No

Equol,microbial

metaboliteofdaidzein

n.a.

Betterthandaidzein

n.a.

Hydroxylationat8and

30 positionsGlcAandsulfate

conjugates

81,82,96

Prenylated

Pyranc(1)

Glabridin

G.glabra

(#3.5mgg1)

Glabridin

detected

inblood

n.d.

n.d.

57,58,61,84,85

Pyranc(1)

Chainb(1)

Hispaglabridin

AG.glabra

n.d.

n.d.

n.d.

61

Pyranc(2)

Hispaglabridin

BG.glabra

n.d.

n.d.

n.d.

61

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Table1

(Contd.)

Prenyl(#

prenyl)

Rem

arks

Dietary

occurrence

Bioavailability

Microbialmetabolites

Phase

IandIImetabolites

Ref.

Pterocarpans

Prenylated

Chainb(1)

GlyceollidinsI/II

Fungus-challenged

soya

sprouts(#

0.2mgg1)

n.d.

n.d.

n.d.

43

Pyranc(1)

GlyceollinsI,II

Fungus-challenged

soya

sprouts(#

7.0mgg1)

Glyceollinsfound

inblood

n.d.

n.d.

43,88,163

Furand(1)

Glyceollin

III

Pyranc(1)

Phaseollin

P.vulgaris(#

0.2mgg1)

n.d.

n.d.

n.d.

157

Isoflavenes

Unprenylated

No

Dehydroequolismicrobial

metaboliteofequol

n.a.

n.d.

n.d.

n.d.

77

Prenylated

Pyranc(1)

Glabrene

G.glabra

n.d.

n.d.

n.d.

61

Coumestans

Unprenylated

No

Coumestrol

Soyfood,sproutsofsoy,

andclover

(#6.0mgg1)

Coumestroldetectedin

urine

samples

n.d.

n.d.

48,5153,56,83

3-Phenylcoumarins

Prenylated

Chainb(1)

Glycycoumarin

G.uralensis

(#2.8mgg1)

GlcAconjugates

(mono,di)detectedin

blood,urineandfeces

n.d.

GlcAconjugates

(mono,di)

87

a-M

ethyldeoxybenzoins

Unprenylated

No

O-desMeangolensin,

60 -O

H-O-desMeangolensin,

both

microbial

metabolitesofdaidzein

n.a.

n.d.

n.d.

n.d.

76,77,99

an.a.,notapplicable;n.d.,notdetermined;diH,dihydro;GlcA,glucuronicacid;Me,methyl.G.max,Glycinemax;G.glabra,Glycyrrhizaglabra;G.uralensis,Glycyrrhizauralensis;L.albus,Lupinus

albus;P.vulgaris,Phaseolusvulgaris;T.pratense,Trifoliumpratense.b3,3-dimethylallyl.

c2,2-dimethyl-chromeno.d200 -isopropenyldihydrofuran.

This journal is The Royal Society of Chemistry 2012 Food Funct., 2012, 3, 810827 | 815

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describing the biotransformation of glabridin by phase II

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. View Article Onlinemetabolism, but this possibility cannot be ruled out, as the

occurrence of metabolites of other prenylated isoflavonoids

(belonging to the subclasses of isoflavones and 3-phenyl

coumarins) has been demonstrated.87 Glabridin and equol are

structurally similar isoflavans, of which glabridin has an addi-

tional pyrano-functionalized A-ring (resulting from cyclisation

of the 7-OH and the 8-prenyl group) and an additional hydroxyl

group on the 20-position. Investigations on bioavailability ofequol showed that a dosage of 2530 mg can result in plasma

levels ranging from 101000 ng mL1 (expressed as total non-

conjugated form).81,82 This might suggest a better bioavailability

for equol than for glabridin. This is surprising, because the

prenyl-moiety confers more lipophilicity to the molecule by

which affinity for membranes, and consequently membrane

passage, was expected to be enhanced. In another study, post-

menopausal female monkeys were fed a soy protein diet enriched

in glyceollins (prenylated pterocarpans).88 Subsequent serum

analysis showed that glyceollins were absorbed and rapidly

cleared after consumption.

From studies with prenylated and non-prenylated phenyl-

benzopyrans other than isoflavonoids, i.e. the single-prenylated

chalcone and flavanone from hop, xanthohumol and iso-

xanthohumol, respectively, it appeared that their absorption is

comparable, given the similar plasma levels found for both sets of

molecules.50,89 Whether the extent of prenylation affects absorp-

tion, remains unclear. The detection of single (as in licoisoflavone

A) and doubly (as in isoangustone A) prenylated isoflavonoid

metabolites in plasma suggests that both forms are absorbed,87

although this does not allow conclusions on the absorption rate.

For prenylated hop bitter acids, in vitro studies indicated that the

presence of a third prenyl substituent, as in b-acids, resulted in

a decreased absorption compared to the doubly prenylated

a-acids.90 Furthermore, the presence of two prenyl groups in

artepillin C, a prenylated hydroxycinnamic acid isolated from

propolis, resulted in a large decrease in bioavailability when

compared to its non-prenylated parent p-coumaric acid.91

Summarizing, prenylated isoflavonoids belonging to different

subclasses (pterocarpans, isoflavans, isoflavones and 3-phenyl

coumarins) indeed appear to be absorbed. When comparing this

data with that of prenylated 2-phenylbenzopyrans, phenolic

acids and bitter acids, it seems as if a single prenyl moiety does

not have a large impact on intestinal absorption, whereas addi-

tional prenyl substituents seem to reduce the bioavailability

considerably. It is evident that the influence of prenyl substitu-

tion, including number and kind of prenyl group, should be

investigated in a more systematic way.

Isoflavonoid transformations by intestinal microbiota


Upon ingestion, isoflavonoids are often metabolised by the

intestinal microbiota. Most studies on isoflavonoid metabolismdetected in plasma in its intact, non-conjugated form, contrary to

equol (isoflavan), genistein and daidzein (both isoflavones) which

are predominantly found in their conjugated forms.86 It must be

emphasized that no attempt was made to determine possible

conjugates or metabolites of glabridin. There are no reports816 | Food Funct., 2012, 3, 810827investigated the major isoflavones from soya and red clover

(Trifolium pratense): daidzein, genistein, glycitein, biochanin A

and formononetin. A common metabolic conversion by the

intestinal microbiota is, for example, demethylation of O-meth-

ylated isoflavones, such as formononetin and biochanin A

(Table 1).92 Furthermore, in vitro and in vivo studies on the

microbial metabolism of isoflavones led to the discovery of

a broad range of metabolites, representing different isoflavonoid

subclasses: equol (isoflavans), dehydroequol (isoflavenes), dihy-

drogenistein (isoflavanones) and (60-hydroxy-) O-desmethy-langolensin (a-methyl deoxybenzoins) (Table 1).7680,9397 Equol

has received special attention as it is considered to be more active

than its precursor molecule, daidzein.86,98 For a more compre-

hensive summary of microbial metabolism of isoflavonoids we

refer to a number of recent reviews.99,100


As far as prenylated isoflavonoids are concerned, there are to our

knowledge no studies from which biotransformation by micro-

biota can be inferred. Several reports describe the microbial

metabolism of prenylated 2-phenylbenzopyrans from hop

(Humulus lupulus). More specifically, isoxanthohumol is deme-

thylated to 8-prenylnaringenin by microbiota, but no modifica-

tion of the prenyl group was observed.101103

Modification of isoflavonoids by phase I and IImetabolism


In addition to intestinal metabolism by microbiota, isoflavones

and their (microbial) metabolites can also undergo oxidative

phase I metabolism resulting in hydroxylation of predominantly

the 6, 8 and 30 positions (Table 1).104,105 The conversion of gen-istein to orobol (or 30-hydroxy genistein) is an example of sucha hydroxylation. Orobol has been found in human tissue and is

slightly less estrogenic than genistein itself.106 Although it was

initially thought that equol was metabolically inert,81more recent

work showed that equol can be metabolised by the liver resulting

in 30-hydroxy and 8-hydroxy equol.96


Only one study investigated the oxidative metabolism of preny-

lated isoflavonoids (Table 1).87 Among the compounds admin-

istered, there was one doubly prenylated isoflavone

(isoangustone A). In addition to its free form and 4 glucuronide-

conjugates, 10 other metabolites of isoangustone A were tenta-

tively assigned: one aldehyde derivative, four monohydroxylated

derivatives, three dihydroxylated derivatives, and two trihy-

droxylated derivatives. Based on mass spectrometry, the prenyl

chain of one of these metabolites was suggested to be oxidised

into an aldehyde derivative. The locations of the various

hydroxyl groups in the other metabolites were not determined.

In vitro studies with liver microsomes have provided an extensive

view on the fate of the prenyl chain of hop 2-phenylbenzopyrans

upon oxidative metabolism.107109 Unfortunately, such studies have

not been done with prenylated isoflavonoids, but it is likely that the

observations with respect to prenyl modification found for hopThis journal is The Royal Society of Chemistry 2012

2-phenylbenzopyrans also apply to prenylated isoflavonoids. It was

shown that the prenyl chain can be modified via two main path-

ways: (1) epoxidation, and (2) hydrogen abstraction, with the

former being the predominant route (Fig. 3). After epoxidation of

the prenyls double bond in pathway 1, various cyclisation products

are formed, ultimately leading to pyran and furan derivatives. In

pathway 2, a radical is formed which is subsequently oxidised

yielding a terminally hydroxylated prenyl chain, either the cis- or

the trans-isomer. The trans-isomer was the most abundant, and

could be further oxidised into an aldehyde. Alternatively, the

double bond in the prenyl chain can migrate leading to mid-chain

hydroxylation of the prenyl group.

Interaction with human ERs

Phytoestrogens

Different kinds of plant-derived compounds are known to induce

biological responses by mimicking or modulating endogenous

estrogens,110 and are, therefore, referred to as phytoestrogens.

They mainly belong to the isoflavonoid subclasses of isoflavones

and coumestans.8,48 Apart from binding to the hER, the estro-

genic activity of phytoestrogens might also result from or be

affected by other mechanisms, such as the induction of sex

hormone-binding globulin (SHBG) or influencing the steroido-111

involved in growth, sexual development and differentiation.110

They also play a role in the regulation of bone formation, the

central nervous system and the cardiovascular system. Two hER

subtypes have been described in humans: hERa and hERb. The

hERa is mainly expressed in the sex organs, such as the endo-

metrium, mammary gland and uterus. The hERb is mainly

expressed in bone, the cardiovascular system, the central nervous

system and the brain.116 Estrogens exert their action by binding

to the ligand-binding domain (LBD) of the receptor, upon which

a dimeric configuration of the receptor is enabled, which facili-

tates binding to estrogen-responsive elements (ERE) on the

DNA (Fig. 4). Binding of the dimeric receptor complex to an

ERE can either stimulate or inhibit gene expression.117

The natural ligands for hERs are C18-steroids, the most well-

known of which is the human sex hormone 17b-estradiol (E2).118

Phytoestrogens exhibit structural similarity with E2, in that they

have an OH-substituted, six-membered carbon ring and

a hydroxyl group at the other end of the molecule. The spacing

between the hydroxyl groups is critical, and should resemble the

1.2 nm between the 3-hydroxyl and 17b-hydroxyl of E2.111,117,119

In general, the phytoestrogens binding affinity is approx. 102 to

105 times weaker than that of endogenous E2 and most phy-

toestrogens preferentially bind hERb.7,120122

n t

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. View Article OnlineFig. 3 Possible routes in prenyl modification by liver metabolism, based o

in red. Structure in bold are those for which there is experimental evidence.

the arrows indicates, by approximation, the importance of that conversioDistribution and activation of human estrogen receptors (hERs)

The hERs belong to the superfamily of nuclear receptors. Their

main function is the regulation of the expression of genesgenesis. Examples of the latter include the inhibition of aro-

matase, 5a-reductase and 17b-hydroxysteroid oxido-reductase

by isoflavonoids.112115 In this review, we will focus on the

binding of isoflavonoids to hERs.This journal is The Royal Society of Chemistry 2012he observations with 8-prenylnaringenin.108 The prenyl group is indicated

hter structures represent putative intermediates or products. Thickness ofhER agonists and antagonists

Nowadays, there is a broad range of in vitro bioassays available

that allow determination of the estrogenic potency of

a compound, ranging from ligand-binding assays to receptor-

dependent gene expression (transactivation) assays and cell

proliferation assays. Whereas the former only determines the

binding affinity of a compound for an ER subtype, the latter two

can also be used to distinguish between agonists andFood Funct., 2012, 3, 810827 | 817

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. View Article Onlineantagonists.123 In all cases, the physiological relevance of the

outcome of in vitro bioassays needs to be confirmed in vivo.

Agonists and antagonists can also be further subdivided into full,

partial or weak based on the extent of transcriptional activation.

Fig. 5 displays typical ER-response curves for full agonistic

and antagonistic ligands. Full agonists are defined as compounds

that induce a 100% transcriptional activation when compared to

E2 (Fig. 5A). Full antagonists induce a conformational change

that hampers dimerization or the recruitment of so-called co-

factors (Fig. 4), resulting in the complete inhibition of DNA

transcription upon co-incubation with E2 (EC70-EC90)

(Fig. 5B).117 Weak agonists and antagonists act as full agonists

and antagonists, but compared to the strong agonists, e.g. E2,

and antagonists, e.g. RU 58668, the concentrations needed to

reach the same agonistic or antagonistic response are much

higher, i.e. higher EC50 (half maximal effective concentration)

and IC50 (half maximal inhibitory concentration) values,

respectively. There are no quantitative values that designate

compounds as weak agonists or antagonists. The response of

partial agonists and antagonists, on the other hand, is incomplete

and does not reach the 100% transcriptional activation (agonist)

or inhibition (antagonists). Partial agonists showing maximal

transcriptional activation up to 30% of that obtained with E2 are

often erroneously called weak estrogens or weak partial estro-

gens, although their EC50 might be lower than that of a strong

partial agonist showing a maximal transcriptional activation of

Fig. 4 Schematic representation of the events occurring upon binding of a

adapted from Lonard and Smith (2002).182 CF, co-factors, e.g. coactivator p

element, a regulatory sequence in the promoter region of target genes; LBD,

transcription machinery.

818 | Food Funct., 2012, 3, 81082780%. Thus overall, the classification weak is used arbitrarily. For

this review, the distinction between full, partial and weak

agonists/antagonists is not further made and they will simply be

referred to as agonist/antagonist.

Although the preferential binding of phytoestrogens to the

hERbmight be relevant for the treatment of osteoporosis, little is

known about their interactions with hERb concerning antago-

nism. Studies on the agonistic and antagonistic activities of

phytoestrogens have mainly focused on hERa, as this is

considered an important target for treatment of certain condi-

tions, e.g. severe (post-)menopausal symptoms and breast

cancer, respectively.124 Investigations regarding the complete

estrogenic profiles of phytoestrogens towards the hERbmight be

considered as a next step in this field of research.

Selective estrogen receptor modulators

Normally, ligands have similar activity in different cell types.

However, several synthetic estrogens are able to display agonistic

activity in one tissue or cell type, and antagonistic activity in

another (Fig. 5C).124 Such ligands are referred to as selective

estrogen receptor modulators (SERMs). The most well-known

SERM representatives are the drugs raloxifene and tamoxifen.

Tamoxifen has been widely used in the treatment of breast cancer

to oppose the proliferative effect of endogenous E2. Therefore, it

was assumed that tamoxifen was a pure antagonist. However,

n agonist (Ag) or an antagonist (Ant) to the human estrogen receptor,

eptides; DBD, DNA-binding domain of hER; ERE, estrogen-responsive

ligand-binding domain of hER; TATA, regulatory sequence for binding

This journal is The Royal Society of Chemistry 2012

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. View Article Onlineprolonged use of tamoxifen resulted in an increased risk of

endometrial cancer development.125 The action of tamoxifen

appeared to be tissue-dependent: overall antagonistic in breast

Fig. 5 A schematic overview of the typical ER-restissue, but agonistic in endometrium and bone (inhibiting oste-

oporosis).126 Raloxifene, used in osteoporosis treatment, has

a different activity spectrum as it acts agonistic in bone and

antagonistic in breast and endometrium.127129

Phytoestrogens, e.g. daidzein and genistein, have occasionally

been suggested to act as SERMs.130132 Their SERM-like

behaviour related to their possible tissue-specific in vivo effects,

exemplified by agonistic activity in bone (inhibiting osteoporosis)

and antagonistic activity in breast tissue (inhibiting breast

cancer). However, both isoflavones acted agonistically towards

both hERs in human breast cancer cell lines.133

These findings imply that there are actually two kinds of

SERMs: true and pseudo SERMs. For the true SERMs, like

tamoxifen and raloxifene, it has been established that they act via

the hERa.125 The action of these true SERMs is most likely

governed by their ability to induce specific conformational states

of hERa or to recruit specific cofactors, depending on cell type.

The action might also be dependent on intracellular conditions,

such as intrinsic estradiol and receptor levels. Even today, the

mode of action of tamoxifen and other SERMs is far from

understood.134 For the pseudo SERMs, there is no evidence that

the observed SERM-like effects in vivo are directly estrogen

receptor mediated. The action of pseudo SERMs might find its

origin in various factors, including modulation of steroidogen-

esis, estrogen synthesis via the extragonadal pathway, hER

expression levels (i.e. affecting the relative abundance of

ER-subtypes in various tissues), or even via other nuclear

receptors (e.g. inhibiting the androgen receptor activity), but not

This journal is The Royal Society of Chemistry 2012or less in modulating the conformational states of hERa.7,135137

Soy isoflavones daidzein and genistein, for example, might be

categorised as members of the pseudo SERMs. These isoflavones

se curves of an agonist, antagonist and a SERM.preferably bind to hERb, and it is assumed that their possible

beneficial effect on osteoporosis is due to activation of this

receptor type in bone. In normal healthy breast tissue expressing

mainly hERa and little hERb, the hERb is thought to act as

a kind of regulator, i.e. suppressing the activity of hERa.122,138

Thus, although both isoflavones have been found to act

agonistically towards both hERs in human breast cancer cell

lines, indirect (not directly related to ligand binding) effects can

oppose the action of these phytoestrogens.133

Although the definition of SERMs implies that at least two

different cell types are needed to explore their characteristics,

sometimes they reveal their identity with only a single cell type.

Some SERMs turn out to be partial agonists. When such SERMs

are tested in combination with a dose of E2 giving the maximal

effect, the agonistic response of E2 in that assay is inhibited to the

level of induction as obtained with the SERM alone, i.e. that of

the partial agonist without E2.139,140 For these SERMs, both their

agonistic and antagonistic properties can be visualized in one

cell type.

Prenylation of isoflavonoids in relation to estrogenicity

Prenylation can transform isoflavonoids into antagonists

The discovery that 8-prenylation of naringenin led to one of the

strongest phytoestrogens with a preferential binding to the

hERa, suggested that prenylation of flavonoids might increase

their estrogenic activity.30,122,141144 This finding initiated studies

Food Funct., 2012, 3, 810827 | 819

Fig.6

SummaryoftherelationshipofthepositionandkindofprenylationoftheisoflavonoidskeletonandhERaactivity(agonist/antagonist),basedontheoverviewinTable2.T

hepositionofagonist

andantagoniststructureswithrespectto

thecentreofthefigure

isarbitrary.


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flavones often resulted in hERa antagonism.145,150152 It has been

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. View Article Onlinesuggested that the bulky prenyl side chain hinders the agonistic

conformation of the hERa.145 This switch of agonism into

antagonism upon prenylation has also been observed in other

isoflavonoid subclasses. The isoflavan equol is considered to be

an hERa-agonist, whereas glabridin, differing only in the pyr-

ano-functionalized A-ring and the 20-hydroxyl group (Fig. 6),appeared to be a hERa-antagonist.133,139,153,154 Also the non-

prenylated glycinol (pterocarpan) is a very potent agonist,

whereas the pyran ring-substituted analogue of glycinol, gly-

ceollin I, appeared to be a potent hERa-antagonist.155 By

molecular modeling, it was shown that glyceollin I docks in the

hERa cavity occupying the same position as the side chain of the

well-known hERa antagonist 4-hydroxy tamoxifen, which is

responsible for its antagonism. No interaction between His524 of

hERa, binding most agonists, and glyceollin I was observed. On

the contrary, glycinol binds His524 and, hence, does not follow

the binding path of the side chain of 4-hydroxy tamoxifen. Thus,

prenylation seems to be responsible for the different docking

poses in the hERa and the subsequent activity, i.e. agonist or

antagonist. Contrary to glyceollin I, the prenylated glyceollins II

and III were reported not to be antagonistic, although both

glyceollin II and III clearly inhibited the E2-induced luciferase in

MCF-7 cells (30%).155 Thus, glyceollins II and III displayedhERa antagonistic activities, although less pronounced than

glyceollin I.

Despite the initial observations with 8-prenylnaringenin, these

pairs of non-prenylated and prenylated molecules, belonging to

different isoflavonoid subclasses, support the hypothesis that

prenylation of isoflavonoids might result in hERa-antago-

nism.122 The prenylated isoflavones alpinumisoflavone and ery-

senegalensein E, on the other hand, have been reported to lack

antagonistic activity.151 Therefore, prenylation does not seem to

lead to antagonism per se.

Position, kind and number of prenyl groups in relation to

estrogenicity

The literature data on the correlation of prenylation of iso-

flavonoids and the kind of estrogenic activity (agonism/antago-

nism) are summarized in Table 2. According to IUPAC, the

carbon numbering of isoflavones differs from that of, for

instance, pterocarpans and coumestans (see Fig. 1), although the

molecules are biosynthetically related. This might erroneously

hint at different substitution patterns of isoflavonoids, whereas

they are actually the same. For example, the 8-prenyl group in

isoflavones has been attached at exactly the same position of theon the effect of prenylation of both 2-phenylbenzopyrans and

isoflavonoids in relation to their estrogenicity. The search for

alternatives in hormone replacement therapy in postmenopausal

women, or in breast and prostate cancer treatment, is a major

topic within the pharmaceutical industry.124,143 The focus in

many of these studies is on hERa, as this is a major determinant

in the development of breast cancer. Several studies with non-

prenylated and various prenylated genistein and daidzein deriv-

atives reported for both isoflavones a major decrease in agonistic

activity, or a decrease in binding affinity, towards both hER-

subtypes upon prenylation.145149 By means of transactivation

and proliferation assays it was shown that prenylation of iso-This journal is The Royal Society of Chemistry 2012from cyclisation of the d-prenyl group and the 4 -OH group),

isolated from an extract of Psoralea corylifolia, might also have

SERM-like behaviour for similar reasons.159 These speculations

are corroborated by the observation that the potent antagonist

glabridin also had potent osteogenic activity.156,160,161 It remains

to be established whether the phytoSERM class in Fig. 6 grows

at the expense of the agonist and antagonist classes.

As phytoSERMs, prenylated isoflavonoids are potentially

interesting phytonutrients. It is clear that additional studies

investigating their structureactivity relationships are necessary

to unravel the precise molecular signatures behind the observed

activities. For this, the estrogenic profiles of prenylated iso-

flavonoids additional to those already studied need to be deter-

mined by assays that are based on different cell or tissue types.

Moreover, these assays need to be characterised in more detail,

e.g. with respect to receptor levels, cross-talk with other recep-

tors, metabolism, and enzymes involved in steroidogenesis, as

these factors can influence the read-out of the assays. Prenylationisoflavonoid skeleton as the 4-prenyl group in pterocarpans. In

order to avoid confusion, the 4 different positions at which

prenylation has been demonstrated have been indicated by

a Greek letter notation, comprising the positions a, b, g, and

d (see also Fig. 6). In general, prenylation at the a-position

appears to promote antagonismmore than that at the b-position,

whereas the kind of prenylation (chain or pyran) seems to be of

secondary importance. The position of prenyl-substitution rather

than the kind of prenylation was also considered of primary

importance to the fungitoxic and insect repellent activity.28

Antagonism is not confined to prenylation of the A-ring. Pre-

nylation at positions g and d also seemed to promote antago-

nism, but these correlations are less clear due to a lack of

representatives that have been tested for antagonism. It remains

unclear whether double prenylation amplifies the antagonistic

effect, as illustrated by the non-estrogenic prenyl-isoflavones

erysenegalensein E and isolupalbigenin (Table 2).

Prenylated isoflavonoids as phytoserms?

Some prenylated isoflavonoids can exhibit agonistic or antago-

nistic activity, depending on the cell type in which the activity

measurement was conducted. For instance, glabridin, containing

an 8-prenyl chain, displayed hERa-antagonism only in an in vitro

yeast estrogen bioassay, but appeared to be an agonist inducing

dose-dependent proliferation in human breast cancer cell lines

(T47D and MCF-7).154,156 This suggests that glabridin shows

assay-dependent estrogenicity. A similar behaviour was observed

for 8-prenylgenistein, kievitone (isoflavanone) and phaseollin

(pterocarpan).150,157 The ability of some prenylated isoflavonoids

to act both as agonist and antagonist, strongly suggests that they

might be classified as phytoSERMs, and this is not limited to one

subclass of isoflavonoids (Table 2 and Fig. 6).

For a number of other isoflavonoids in Table 2 SERM-like

behaviour might be expected, given the probability that pre-

nylation might induce antagonistic activity (Table 2) and their

known agonistic activity in osteosarcoma cells (U2OS and

UMR106). Several derivatives of genistein combine prenylation

and osteogenic activity, i.e. the single (isopoegin B and D), and

the doubly prenylated (6,8-diprenylgenistein).149,158 Moreover,

corylin (daidzein with pyrano-functionalized B-ring, resultingFood Funct., 2012, 3, 810827 | 821

Table2

Theinfluenceofthepatternofprenylsubstitutionofvariousisoflavonoidsontheagonist/antagonistactivitytowardsthehERa.Withtheisoflavones,focusliesonthepredominantisoflavones

occurringin

GlycinemaxandTrifoliumpratense

asthemain

dietary

contributors.a

Trivialname

Estrogeniccharacteristics

Overalltype

Ref.

Molecularcharacteristics

Humancellline

YeastR

1stprenylPos.

2ndprenyl

Pos.

Origin

Type

Action

Action

Isoflavones

Unprenylated

Daidzein

G.max;T.pratense

IshikawabP

Agonist

Agonist

Agonist

6,133,151

Genistein

G.max;T.pratense

IshikawabP;

MCF-7

PAgonist

Agonist

Agonist

6,133,139,

150,151

Glycitein

G.max;T.pratense

MCF-7

PAgonist

Noagonisti

Agonist

164

Form

ononetin

G.max;T.pratense

VariousPassays

Agonist

Agonist

Agonist

6Biochanin

A

G.max;T.pratense

VariousPassays

Agonist

Agonist

Agonist

6Ipriflavoned

Chem

icalsynthesis

RLBA;MCF-7

PNoagonist

Noagonisti

Notestrogenic

121,139,165

Prenylated

8-Prenyl-form

ononetin

Chain

a

O.ebenoides

MCF-7

P+R

Noagonist

Notestrogenic

i146

8-Prenylgenistein

Chainh

a

M.philippinensis;

E.variegata

MCF-7

PAntagonist

Antagonist

PhytoSERM

150,158

UMR106P

Agonist

7,8-(2,2-diM

e-pyrano)

daidzein

Pyran

a

Chem

icalsynthesis

MCF-7

RAntagonist

Antagonist

145

6-Prenylgenistein

Chain

b

M.pachycarpa;

E.variegata

UMR106P

n.d.j

n.d.j

n.d.j

151,158

Alpinumisoflavone

Pyran

b

M.pachycarpa

Noagonist;

noantagonist

Notestrogenic

151

Kwakhurin

Chain

g

P.mirifica

MCF-7

PAgonist

Agonisti

166

Isopoegin

BChain

d

E.poeppigiana

U2OSR

Agonist

Agonisti

149

Isopoegin

DPyrane

d

E.poeppigiana

U2OSR

Agonist

Agonisti

149

Corylin

Pyran

d

P.corylifolia

UMR106P

Agonist

Agonisti

159

6,8-D

iprenyl-genistein

Chain

aChain

bE.variegata

UMR106P

Agonst

Agonisti

158

6,8-D

iprenyl30 -O

Hgenistein

Chain

aChain

bM.philippinensis;

M.pachycarpa

MCF-7

PAntagonist

Antagonist

Antagonist

150,151

Isoerysenegalensein

EChain

aChaink

bM.pachycarpa

Antagonist

Antagonist

151

Erysenegalensein

EChaink

aChain

bM.pachycarpa

Noagonist;

noantagonist

Notestrogenic

151

Millewanin

GChain

aChaink

bM.pachycarpa

Antagonist

Antagonist

167

Millewanin

HChaink

aChain

bM.pachycarpa

Antagonist

Antagonist

167

Warangalone

Chain

aPyran

bM.pachycarpa

Antagonist

Antagonist

151

Auriculasin

Chain

aPyran

bM.philippinensis;

M.pachycarpa

MCF-7

PAntagonist

Antagonist

Antagonist

150,151

Furowanin

AChain

aFuranl

bM.pachycarpa

Antagonist

Antagonist

151

Furowanin

BFuranl

aChain

bM.pachycarpa

Antagonist

Antagonist

167

Isolupalbigenin

Chain

aChain

dE.poeppigiana

U2OSR

Noagonist

Notestrogenic

i149

20 ,5

0 -Diprenyl30 OH

genistein

Chain

gChain

dM.philippinensis

MCF-7

PAntagonist

Antagonist

Antagonist

150

20 -P

renyl40 ,5

0 -(2,2-diM

e-pyrano)30 -O

Hgenistein

Chain

gPyran

dM.philippinensis

MCF-7

PAntagonist

Antagonist

Antagonist

150


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Table2

(Contd.)

Trivialname


Overalltype

Ref.


Humancellline

YeastR

1stprenylPos.

2ndprenyl

Pos.

Origin

Type

Action

Action

Isoflavanones

Unprenylated

Derivatives

of7,40 -d

iOH

isoflavanone

D.parviflora

MCF-7P+R;T

47DP

+R

Agonist

Agonisti

168,169

DiH

daidzein

Microbialmetabolite

MCF-7

P;293hEK

RAgonist

Noagonisti

Agonisti

164,170

DiH

genistein

Microbialmetabolite

MCF-7

P;293hEK

RAgonist

Agonisti

170

Prenylated

Kievitone

Chain

a

P.vulgaris

MCF-7

RAgonistand

antagonist

PhytoSERM

157

Isoflavans

Unprenylated

Equol

Microbialmetabolite

MCF-7

P;

IshikawabP

Agonist

Agonist

Agonist

133,139,153

Vestitol

D.parviflora

MCF-7

P+R;

T47D

P+R

Agonist

Agonisti

169

Mucronulatol

D.parviflora

MCF-7

P+R;

T47D

P+R

Agonist

Agonisti

169

50 -O

Mevestitol

D.parviflora

MCF-7

P+R;

T47D

P+R

Agonist

Agonisti

169

Prenylated

Glabridin

Pyran

a

G.glabra

MCF-7

P+R;

T47D

P+R

Agonist

Antagonist

PhytoSERM

154,156,171

Glabridin

40 -M

eether

Pyran

a

G.glabra

MCF-7

P;T47D

PAgonist

Agonisti

156

Glabridin

20 -M

eether

Pyran

a

Sem

isynthetic

MCF-7

P;T47D

PAgonist

Agonisti

156

Glabridin

2,0 4

0 -DiM

eether

Pyran

a

Sem

isynthetic

MCF-7

P;T47D

PAgonist

Agonisti

156

TetraH

glabrene

Pyrang

d

Chem

icalsynthesis

RLBA

Estrogenic

Estrogenici ,p

172

Hispaglabridin

APyran

aChain

dG.glabra

RLBA

Estrogenic

Estrogenici ,p

171

Hispaglabridin

BPyran

aPyran

dG.glabra

RLBA

Estrogenic

Estrogenici ,p

171

Pterocarpans

Unprenylated

Glycinol

G.max

MCF-7

RAgonist

Agonist

173

Pisatin

P.sativum;

Tephrosiaspp.

RLBA

Estrogenic

Estrogenici ,p

62,174,175

Medicarpin

Medicagossp.

MCF-7

PAgonist

Agonist

Agonisti

176178

Maackiain

S.flavescens

RLBA

Nobinding

Notestrogenici

179

Prenylated

Bitucarpin

AChain

a

B.bituminosa

Antagonist

Antagonist

152

Glyceollin

IPyran

a

G.max

MCF-7

RAntagonist

Antagonist

88,155,180

Glyceollin

IIPyran

b

G.max

MCF-7

RAntagonistm

Antagonistm

88,155

Glyceollin

III

Furanf

b

G.max

MCF-7

RAntagonistm

Antagonistm

88,155

Glyurallin

AChain

b

P.mirifica

MCF-7

PNoagonist

Notestrogenic

i166

Puem

iricarpene

Chain

g

P.mirifica

MCF-7

PNoagonist

Notestrogenic

i166

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Table2

(Contd.)

Trivialname


Overalltype

Ref.


Humancellline

YeastR

1stprenylPos.

2ndprenyl

Pos.

Origin

Type

Action

Action

(+)-Tuberosin

Pyran

d

P.mirifica

MCF-7

PNoagonist

Notestrogenic

i166

Phaseollin

Pyran

d

P.vulgaris

MCF-7

RAgonistand

antagonist

PhytoSERM

157

Isoflavenes

Prenylated

Glabrene

Pyran

d

G.glabra

MCF-7P+R;T

47DP

+R;RLBA

Agonist

Agonistc

Agonist

154,171,172

Coumestans

Unprenylated

Coumestrol

G.max

IshikawabP

Agonist

Agonist

Agonist

133,139

Prenylated

Glycyrol

Chain

b

G.uralensis

RLBA

Estrogenic

Estrogenici ,n,p

172

Coumarono-chromones

Prenylated

TriquetrumoneC

Pyran

aPyrano

gT.triquetrum

RLBA

Estrogenic

Estrogenici ,p

181

adiH,dihydro;tetraH,tetrahydro;Me,methyl;P,proliferationassay;R,genereporter

assay;RLBA,receptorligand-bindingassay.B.bituminosa,Bituminariabituminosa;D.parviflora,Dalbergia

parviflora;E.variegata,Erythrinavariegata;E.poeppigiana,Erythrinapoeppigiana;G.max,Glycinemax;G.glabra,Glycyrrhizaglabra;G.uralensis,Glycyrrhizauralensis;M.pachycarpa,Miletta

pachycarpa;M.philippinensis,Moghania

philippinensis;O.ebenoides,Onobrychisebenoides;P.vulgaris,Phaseolusvulgaris;P.sativum,Pisum

sativum;P.corylifolia,Psoraleacorylifolia;P.mirifica,

Puerariamirifica;S.flavescens,Sophora

flavescens;T.triquetrum,Tadehagitriquetrum.bIshikawacellsare

basedonanadenocarcinomacellline.

cGlabrenewastested

asapurified

fractionand

should

betested

inpure

form

toaccurately

determineitsestrogenicactivity.dIpriflavoneisconsidered

asyntheticisoflavonewithestrogenicactivitiesthatare

possibly

mediatedthroughother

pathwaysthanER.121e2,2-dimethyl3-hydroxychromano.f200 -isopropenylfuran.g2,2-dimethylchromano.h1,1-dimethylallyl.

iAntagonisticactivitynotdetermined.jNotdetermined

inassay

dueto

cytotoxicity.k2-hydroxy3-m

ethylbut-3-enyl.

l200 -(2-hydroxy-)isopropenyldihydrofuran.mGlyceollinsII

andIIImightbeconsidered

aspartialantagonists.n>500times

weaker

binding

thancoumestrol.

o2,2-dimethyl3,4-dihydroxychromano.pEstrogenicityonlymeasuredbyER-binding.

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. View Article Online824 | Food Funct., 2012, 3, 810827 This journal is The Royal Society of Chemistry 2012

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. View Article Onlineoften modulates the estrogenicity from agonism into antago-

nism. As yeast-based assays do not suffer from cross-talk with

other nuclear receptors and are devoid of steroid metabolism, the

observed responses are highly specific for effects directly medi-

ated by the ER. Therefore, 8-prenylgenistein and glabridin, for

example, might be considered as true phytoSERMs (Table 2).

Furthermore, future investigations should not be limited to

only the hERa, but also focus on the hERb. In view of the

current developments regarding new health ingredients for

functional foods and food supplements, there is a growing

interest in novel phytoestrogens. This interest is fuelled by the on-

going search for new SERMs by the pharmaceutical industry,

looking for alternatives to treat menopausal complaints,

hormone-dependent cancers and osteoporosis. With their unique

estrogenic profile, botanical sources rich in prenylated iso-

flavonoids are potentially interesting for development of such

new products.

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