Plant isoflavones' effect on human cancers
Dietary estrogenic isoflavones are potent inhibitors of
beta-hydroxysteroid dehydrogenase of P. testosteronii.
Keung WM. Biochem Biophys Res Commun 1995 Oct 24 215:3
1137-44
Abstract
The isoflavones daidzein, genistein, biochanin A and formononetin
selectively inhibit the gamma-isozymes of mammalian alcohol
dehydrogenase (ADH).
Since gamma-ADH is the only ADH isoform that catalyzes 3
beta-hydroxysteroid oxidation, it was conjectured that these
isoflavones might also inhibit other enzymes involved in 3
beta-hydroxysteroid metabolism. P. testosteronii beta-hydroxysteroid
dehydrogenase (beta-HSD) was used to evaluate this hypothesis.
Indeed, all isoflavones that inhibit gamma-ADH were found to be
potent inhibitors of beta-HSD. Both the 3 beta- and 17 beta-HSD
activities of the enzyme are inhibited.
Kinetic analyses with pregnenolone (3-beta-OH) and testosterone
(17-beta-OH) as substrates reveal that daidzein and genistein inhibit
beta-HSD competitively with respect to the sterol substrates. Their Ki
values are very similar and range from 0.013 to 0.02 microM.
These results suggest that isoflavones may exert some of their
biological effects by modulating activities of enzymes that metabolize
steroids critical to hormonal and/or neuronal functions.
Estrogen-specific 17 beta-hydroxysteroid oxidoreductase type 1
(E.C. 1.1.1.62) as a possible target for the action of
phytoestrogens.
Mäkelä S, Poutanen M, Lehtimäki J, Kostian ML, Santti R, Vihko R.
Proc Soc Exp Biol Med 1995 Jan 208:1 51-9.
Abstract
Several plant estrogens, especially coumestrol and genistein, were
found to reduce the conversion of [3H]estrone to [3H] 17 beta-estradiol
catalyzed by estrogen-specific 17 beta-hydroxysteroid oxidoreductase
Type 1 (E.C. 1.1.1.62) in vitro.
Coumestrol, the most potent inhibitor in our experiments, is the
best inhibitor of the enzyme known to date.
All compounds with inhibitory effects were also estrogenic. However,
structural demands for 17 beta-HSOR Type 1 inhibition and estrogenicity
of tested compounds in breast cancer cells (judged by increased cell
proliferation) were not identical.
Zearalenone and diethylstilbestrol, both potent estrogens, did not
inhibit 17 beta-HSOR Type 1. Thus, changes in the estrogen molecule may
discriminate between active sites of 17 beta-HSOR Type 1 and estrogen
binding sites of the ER. The effects of these compounds in vivo cannot
be predicted on the basis of these results.
Inhibition of 17 beta-HSOR Type 1 enzyme could lead to a decrease in
the availability of the highly active endogenous estrogen. However,
these compounds are estrogenic per se, and they may thus replace
endogenous estrogens.
Additional studies are needed to further understand the role of
these plant estrogens in the etiology of hormone-dependent cancers. It
is not easily conceivable how the chemopreventive action of Asian
diets, possibly mediated by phytoestrogens in soya products, can be
based on the inhibition of estrone reduction at the target cells by
phytoestrogens or related compounds, unless they are ''incomplete
estrogens'' (i.e., unable to induce all effects typical of endogenous
estrogens).
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