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Journal of Steroid Biochemistry & Molecular Biology 93 (2005) 285–292
Inhibition of 17beta-hydroxysteroid dehydrogenases by phytoestrogens:
Comparison with other steroid metabolizing enzymes
D. Deluca a , A. Krazeisen a , R. Breitling b , C. Prehn a , G. Möller a , J. Adamski a, ∗
a
GSF-National Research Center for Environment and Health, Institute for Experimental Genetics, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
b University of Glasgow, Molecular Plant Sciences Group and Bioinformatics Research Centre,
Institute of Biomedical and Life Sciences, Glasgow G12 8QQ, UK
Abstract
Effects of phytoestrogens on human health have been reported for decades. These include not only beneficial action in cancer prevention
but also endocrine disruption in males. Since then many molecular mechanisms underlying these effects have been identified. Targets of
phytoestrogens comprise steroid receptors, steroid metabolising enzymes, elements of signal transduction and apoptosis pathways, and even
the DNA processing machinery. Understanding the specific versus pleiotropic effects of selected phytoestrogens will be crucial for their
biomedical application. This review will concentrate on the influence of phytoestrogens on 17beta-hydroxysteroid dehydrogenases from a
comparative perspective with other steroid metabolizing enzymes.
© 2004 Elsevier Ltd. All rights reserved.
Keywords: 17beta-Hydroxysteroid dehydrogenase; Phytoestrogens; Flavonoids
1. Role of phytoestrogens in human health
Epidemiological studies comparing disease incidence in
countries with high-quality health care have shown striking geographic differences in the occurrence of not only
hormone-related types of cancer such as breast and prostate
cancers [1–3] but also cancers of the digestive tract [4], and
hormone-dependent cardiovascular diseases [5], and also in
the progression of post-menopausal-related diseases [6–12].
The incidence of these diseases is significantly lower in
Asia compared to Northern Europe and America [13–15].
These studies suggest that environmental factors, especially
dietary components, have a major impact on the development
and progression of several cancer types and other hormonerelated diseases. One class of substances are suggested to be
responsible for these protective effects. These are the phytoestrogens which are particularly abundant in soy products,
a major component of the Asian diet. They are functionally
Abbreviations: 17␤-HSD, 17beta-hydroxysteroid dehydrogenase; P450,
cytochrome P450
∗ Corresponding author. Tel.: +49 89 3187 3155; fax: +49 89 3187 3225.
E-mail address: [email protected] (J. Adamski).
0960-0760/$ – see front matter © 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jsbmb.2004.12.035
defined as substances found in plants that promote estrogenic
actions in animals [16].
2. Role of phytoestrogens in plants
Phytoestrogens are a chemically diverse set of compounds and not all their biological roles in plants are fully
understood. However, some of them are thought to act as
natural fungicides, UV-protectants, anti-oxidants and flower
pigments, and also to participate in pollen germination and
stress signalling [17–23].
3. Sources of phytoestrogens
Phytoestrogens not only can be found in any plant or plantderived product, but are also detectable in water as a result
of plant decomposition. They can be divided into three main
classes: flavonoids, coumestans and lignans. Most of them
are diphenolic substances usually with structural similarity
in their three-dimensional conformation to the natural human
steroid hormones. The group of flavonoids comprise flavones,
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D. Deluca et al. / Journal of Steroid Biochemistry & Molecular Biology 93 (2005) 285–292
Table 1
Phytoestrogens reveal pleiotropic effects on single targets and regulatory pathways
Substance
Target
Effect
Reference
Lignans, isoflavones
Genistein, naringenin
Flavonoids, lignans
Quercetin
Formononetin, genistein, biochanin
A, daidzein, and equol
Flavonoids
Daidzein, genistein, coumestrol
Isoflavones
alpha-Fetoprotein
Sex hormone-binding globulin (SHGB)
Steroid receptors
Guanylate cyclase
MAP kinase
Hormone displacement
Hormone displacement
Activation
Activation
Inhibition
[58]
[59]
[39,60–62]
[63]
[64]
Protein kinase B
Prostaglandin synthase
Vitamin D synthesis (CYP24 and CYP27B1
transcriptional inhibition)
Sulfatase
Sulfotransferase
3beta-Hydroxysteroid dehydrogenase
delta5/delta4 isomerase
Aromatase P450 (CYP19A1)
11beta-Hydroxysteroid dehydrogenase 1
17beta-Hydroxysteroid dehydrogenases
5alpha-Reductase
Caspase-3 and -8
Topoisomerase II
Inhibition
Activation
Activation
[65,66]
[67]
[36,68,69]
Inhibition
Inhibition
Inhibition
[70]
[70,71]
[46,72]
Inhibition
Inhibition
Inhibition
Inhibition
Cleavage promotion
Inhibition
[46,73,74]
[56,75]
[46,47,49–51]
[38,76]
[37]
[77]
Daidzein
Quercetin, genistein
Isoflavones, flavonoids
Flavonoids
Flavanone
Flavonoids
Isoflavones
Daidzein
Coumestrol, genistein
flavanones and isoflavones. Flavonoids are found in almost
all plant families in leaves, stems, roots, flowers and seeds
[22,24].
The main dietary source for isoflavones is the soybean,
containing the glycoside of genistein among others. Flavones
and flavanones are widely distributed in all plant families and
are found in fruits, vegetables, berries, herbs, beans, and green
tea. Most of the flavonoids found in plants are present as glycosides, but only the aglycones exert estrogen-like activities
after their release by hydrolytic cleavage during digestion.
High levels of coumestrol are found in alfalfa and various
beans [8]. The plant lignans are instead found in fibre-rich
food, such as unrefined grain products, and are transformed
by intestinal bacteria into mammalian lignans such as enterolactone and enterodiol [25].
Additional dietary estrogenic compounds are the resorcyclic acid lactones, e.g. zearalenone which occur as secondary metabolites in mold-infected food [26].
4. Concentrations of phytoestrogens in humans
Beans, especially soybeans, are a major nutritional component in the Asian diet. A calculation of the approximate
intake of isoflavones by rural Japanese men gave a mean
value of about 6 mg daidzein and 10 mg genistein per day.
These men have very high concentrations of isoflavones in
their plasma [27–30]. The highest individual value exceeded
2 ␮M. Compared to these high levels, the concentration of
these flavonoids in urine and plasma in men living in Europe is very low. The mean plasma value in Finnish subjects
for daidzein and genistein is about 5 nM each [31]. After
consumption of 20 g roasted beans, the following peak concentrations were observed: 0.2 ␮M in human milk, 2 ␮M in
plasma and 20 ␮M in urine [23]. Local tissue concentrations
are expected to be two- to three-fold higher. These differences
in the concentrations are around three orders of magnitude,
and the high concentrations found in the Asian population
are in a range that might influence estrogen signalling. These
data should attract attention to these substances and to their
possible application for treating disorders associated to estrogens.
5. Targets of phytoestrogens
The effects of phytoestrogens were reported controversially: Potential activities as endocrine disruptors in males
were described in several studies [32–34]. On the other hand,
beneficial influence could be observed as well: beneficial role
in the modulation of progression of breast and prostate cancers [3,35], enhancement of vitamin D-mediated inhibition of
tumour progression [36], alternative to hormone replacement
therapies [6], down-regulation of osteoclast differentiation
[37], and improvement of neuronal protection and memory
[35,38]. Several in vitro and in vivo studies identified various
modes of action for phytoestrogens. They modulate signal
transduction by the estrogen receptors (alpha and beta), the
aryl hydrocarbon receptor, the pregnane X-receptor, the constitutive androstane receptor and the peroxisome proliferatoractivated receptors (alpha and gamma) [3,39], and influence
transport proteins, kinases and further enzymes, as shown in
Table 1.
6. Function of 17beta-hydroxysteroid
dehydrogenases
Pre-receptor regulation of steroid hormone action is controlled by hydroxysteroid dehydrogenases and reductases
D. Deluca et al. / Journal of Steroid Biochemistry & Molecular Biology 93 (2005) 285–292
converting steroids at positions 3, 5, 11, 17 and 20 of the
steroid backbone [40–43]. The subject of this review is
the influence of phytoestrogens on 17beta-hydroxysteroid
dehydrogenases (17␤-HSD) in comparison to other steroid
metabolising enzymes. By conversion at position 17 of the
steroid molecule the 17␤-HSDs modulate the biological
potency of estrogens and androgens: the keto-forms are
inactive whereas the hydroxy-forms are active and access
the receptors (Fig. 1). 17␤-Hydroxysteroid dehydrogenases
belong to two protein superfamilies: SDR (short-chain
dehydrogenase/reductase) and AKR (aldo-ketoreductase)
[41,44]. Ten types of human 17␤-HSDs have been described
to date varying in substrate specificity and tissue distribution
[45]. 17␤-HSD 5 is unique among this group of enzymes as
it belongs to the AKR family, while the rest of the 17␤-HSDs
belongs to the SDR superfamily [45].
287
genases versus other enzymes of steroid metabolism. Given
the pleiotropic and sometimes adverse effects of phytoestrogens, understanding the differences in specificity and their
molecular basis will be crucial for the development of efficient biomedical applications.
7.1. 3beta-HSD/delta5/delta4 isomerase versus
aromatase and 17β-HSD 1
In a comparative study in human placental microsomes Le
Bail et al. [46] tested phytoestrogens for inhibition of P450
aromatase, 3␤-hydroxysteroid dehydrogenase-delta5/delta4
isomerase and 17␤-HSD 1 (Fig. 1). Isoflavonoids and
compounds which presented the phenolic B ring at
position 3 of the pyran ring preferentially inhibited 3betaHSD/delta5/delta4 isomerase and/or 17␤-HSD activities
over aromatase activity [46]. However, 7-hydroxy-flavone
and apigenin (for structures see Fig. 2) were the most effective aromatase and 17␤-HSD 1 inhibitors, respectively [47].
7. Comparison of inhibition of hydroxysteroid
dehydrogenases by phytoestrogens with other steroid
metabolizing enzymes
7.2. Aromatase and 17β-HSD 1
In the following we will present a comparative overview
of the effects of phytoestrogens on hydroxysteroid dehydro-
Selected phytoestrogens were checked for aromatase and
17␤-HSD 1 activity modulation in primary cultures of hu-
Fig. 1. This simplified section of steroid conversions involving 17beta-, 3beta-, 3alfa-HSDs and aromatase activities. Simplified part of steroid metabolism is
annotated with enzymes catalyzing reactions inhibited by phytoestrogens. Steroid numbering: dehydroepiandrosterone (1), androstenedione (2), estrone (3),
estradiol (4), testosterone (5), dihydrotestosterone (6), androstanediol (7), androsterone (8).
288
D. Deluca et al. / Journal of Steroid Biochemistry & Molecular Biology 93 (2005) 285–292
Fig. 2. Chemical formulas of the most potent inhibitors of steroid metabolizing enzymes. Chemical structures (A) are given together with 3D-representations
(B). All molecules are shown in the same orientation as the natural substrates. Numbering: estradiol (4), testosterone (5), 7-hydroxy-flavone (9), flavanone
(10), apigenin (11), kaempferol (12), coumestrol (13), quercetin (14), abietic acid (15), zearalenone (16). 3D-coordinates were prepared in ChemDraw Pro and
graphics rendered in iMOL. Corresponding PDB files are available from the authors upon request.
man granulosa-luteal cells by Whitehead et al. [48]. Apigenin and zearalenone significantly inhibited the aromatase
activity, while biochanin A and quercetin had no effect. None
of the phytoestrogens inhibited FSH-induced 17␤-HSD 1 activity, and only quercetin significantly inhibited progesterone
production.
7.3. 17β-HSD 1 and 17β-HSD 2
Makela et al. [49,50] studied the effects of several
flavonoids and isoflavonoids on 17beta-oxidoreduction of estrogens by purified 17␤-HSD 1 and in cell lines expressing
17␤-HSD 1 (T-47D breast cancer cells) or 17␤-HSD 2 (PC-3
prostate cancer cells). Several conclusions could be drawn
in light of the reported results about these phytoestrogens.
Flavones, flavanones, and isoflavones hydroxylated at both
the double ring (positions 5 and 7) and ring B (position 4 )
were the most potent inhibitors of estrone reduction (17␤HSD 1 activity) in T-47D cells, the best being apigenin and
coumestrol. The same results were found with purified 17␤HSD 1. Flavones hydroxylated at positions 3, 5 and 7 of rings
A and C, with or without a hydroxyl group in ring B, were ca-
pable of inhibiting estradiol oxidation (17␤-HSD 2 activity)
in PC-3 cells. Changes to the flavanone structure, or hydroxylation at position 3 of ring C of flavones, or methylation
of the hydroxyl group at position 4 of ring B of flavones
and isoflavones reduced or abolished their inhibitory activity on estrone reduction in T-47D cells. In contrast, the hydroxyl group at position 3 of flavones markedly increased the
inhibition of estradiol oxidation in PC-3 cells, kaempferol
being in this case the best inhibitor. Thus, changes in the
number and location of hydroxyl groups may discriminate
between inhibition of estrone reduction and estradiol oxidation. Some of the differences may be due to differences
in the pharmacokinetics of these compounds in T-47D and
PC-3 cells. Regarding prevention or treatment of estrogenrelated diseases, the substances apigenin, coumestrol, and
genistein raise special interest considering the results
so far.
7.4. 17β-HSD 5
The influence of phytoestrogens (flavonoids, coumarins,
coumestans) on the reductive (androstenedione to testos-
D. Deluca et al. / Journal of Steroid Biochemistry & Molecular Biology 93 (2005) 285–292
terone) and oxidative (androstanediol to androsterone)
17␤-activity of the recombinant purified human 17␤-HSD
5 was tested by Krazeisen et al. [51]. The best inhibitors
for the reductive activity were zearalenone, coumestrol,
quercetin and biochanin A (IC50 4 ␮M, 4 ␮M, 9 ␮M and
14 ␮M, respectively). The oxidative activity was inhibited
most strongly by zearalenone, quercetin, 7-hydroxy-flavone
and biochanin A (IC50 2 ␮M, 5 ␮M, 7 ␮M and 8 ␮M,
respectively). Among the group of flavones the inhibitor
potency is growing with increasing number of hydroxylations in ring A, the most effective being a hydroxylation at
position 7.
For flavonoids the issue is more complex due to the presence or absence of a double bond in ring C, the position of
ring B as well as the hydroxylation pattern. Under reductive
conditions a double bond in ring C increases the inhibitory
potency (e.g. naringenin versus apigenin). In contrast, the flavanones (lacking the double bond) have stronger influence on
the oxidative activity of 17␤-HSD 5. For both 17␤-hHSD 5
activities, inhibitor potency decreases when ring B is found
at position 3 as it is in isoflavones. Flavones carrying a 5methoxy group at ring A are more potent than those with a
hydroxy group at this position. However, within the group
of flavones methylation of position 5 increases inhibition of
the reductive pathway but decreases activity in oxidative conversion. Within the group of isoflavones methylation of the
hydroxy group at position 4 correlates with a high inhibitor
activity.
On the other hand, substances like the synthetic antiestrogens tamoxifen, diethylstilbestrol, daidzein and coumarin had
no influence on both types of reaction. An interesting inhibition pattern is observed for 18␤-glycyrrhetinic acid with
17␤-HSD 5, as in this case this compound has no influence on the oxidative, but only on the reductive reaction
of the enzyme. This result could be explained with a deprotonation of the His 117 in the active center at higher
pH values, at which the oxidation tests were performed in
vitro. The deprotonated side chain of His 117 is then unable to bind the substrate 18␤-glycyrrethinic acid. This indicates that this substrate binds at the active center of the
enzyme in a pH- and cofactor-dependent way [51]. The
proposed model can now be further analysed in light of
289
the recently determined crystal structure of 17␤-HSD 5
[52].
The dietary substances described above shown to be potent inhibitors of 17␤-HSD 5 seem to play an important role
in delaying the development of hormone-dependent cancers
such as that of prostate carcinoma.
7.5. 11β-HSD and 17β-HSD and 17,20-lyase
The inhibitory capacity of 18␤-glycyrrhetinic acid, contained in licorice, has been firstly observed toward 11␤-HSD
(Fig. 3) [53] and later toward other enzymes as well, as it is
reported above with 17␤-HSD5. Previously it has been reported that the serum testosterone level in men consuming
about 7 g of a commercial preparation of licorice (containing
0.5 g of 18␤-glycyrrhetinic acid) a day is significantly reduced [54]. The inhibitory effect of 18␤-glycyrrhetinic acid
may be the reason for that, since it has been demonstrated
that licorice consumption inhibits 11␤-HSD [55], 17␤-HSD
and 17,20-lyase activity (Fig. 4) [54]. Decreased testosterone
levels result in reduced libido or other sexual dysfunctions but
might have beneficial effects in cases of abnormal prostate
growth.
7.6. 11β-HSD 1 and 11β-HSD 2
Abietic acid inhibited both 11␤-HSD 1 (IC50 27 ␮M
for reduction and 2.8 ␮M for oxidation) and 11␤-HSD 2
(IC50 12 ␮M). Flavanone and 2 -hydroxyflavanone efficiently
(IC50 18 and 10 ␮M, respectively) inhibited reductive but not
oxidative activity of 11␤-HSD 1 as shown by Schweizer et
al. [56]. These assays were performed with lysates of cells
stably transfected with 11␤-HSD 1 and 11␤-HSD 2. This observation reveals that a variety of environmental compounds
exert distinct inhibitory effects on 11␤-HSD 1 and 11␤HSD 2, opening the possibility for selectively modulating
local cortisone/cortisol availability in vivo. Amide derivatives of the 18␤-glycyrrethinic acid at position 30 were studied as possible inhibitors of 11␤-HSD 1 and 11␤-HSD 2.
The study opens the way to a new class of substances and a
specific inhibitor for 11␤-HSD 2 has already been identified
[57].
Fig. 3. Steroid conversions at position 11beta. Steroid numbering: cortisol (17), cortisone (18).
290
D. Deluca et al. / Journal of Steroid Biochemistry & Molecular Biology 93 (2005) 285–292
References
Fig. 4. Activity of 17-hydroxylase, 17,20-lyase. Steroid numbering: pregnenolone (19), 17-hydroxy-pregnenolone (20), dehydroepiandrosterone (1).
8. Conclusion
Although phytoestrogens can inhibit quite a broad
spectrum of steroid metabolizing enzymes, there is always an enzyme-specific preference. For example, 18␤glycyrrethinic acid is a potent inhibitor of 11␤-HSDs but
not a very effective modulator of 17␤-HSDs. Future work
should be able to exploit our improved understanding of these
specific effects for the development of targeted inhibitors of
steroid metabolism.
Acknowledgement
This work was supported in part by a DFG grant to Jerzy
Adamski.
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