Estrogen-Specific 17 -Hydroxysteroid Oxidoreductase Type 1 (E.C. 1.1.1.62) as a Possible Target for the Action of Phytoestrogens

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).

Dietary soy-phytoestrogens decrease testosterone levels and prostate weight without altering LH, prostate 5alpha-reductase or testicular steroidogenic acute regulatory peptide levels in adult male Sprague-Dawley rats

“…On the other hand, the inter-conversion of testosterone to androstenedione is regulated by the activity of 17 -hydroxysteroid dehydrogenase, an enzyme that has been shown to be influenced by phytoestrogens (Makela et al 1995b). Changes in plasma androstenedione levels with the Phyto-600 diet were much lower compared with those observed for testosterone by dietary treatments, suggesting that the substrate supply or enzyme regulation for testosterone synthesis may be affected by the phytoestrogen-rich diet.…”

Cross-species and interassay comparisons of phytoestrogen action.

“…Micromolar concentrations are required for lignan and isoflavone binding to SHBG (5-50 µM) (38) and α-fetoprotein (K d : 0.5-5 µM) (57,58). Concentrations required for inhibition of most steroid metabolizing enzymes are generally in the micromolar range, with the exception 17β-hydroxysteroid dehydrogenase type I, which is inhibited by isoflavonoids at concentrations ranging from 120 nM to 1 µM (33,59).…”

“…A variety of in vitro assays have now shown that isoflavones and lignans are inhibitors of aromatase (30,31) and 5α-reductase (32). A number of phytoestrogens also inhibit 17β-hydroxysteroid dehydrogenase Type I (33).…”

“…However, the very high concentrations required for inhibition by isoflavones (Table 3) make it unlikely that they would significantly influence estrogen production in the ovary. A more likely route for isoflavone influences on E 2 bioavailability would be via inhibition of 17-hydroxysteroid dehydrogenase type I, an effect that occurs at concentrations of 0.1-1 µM (33,59). In addition, phytoestrogens could augment or inhibit estrogen negative feedback by binding to ERs in the anterior pituitary or hypothalamus and indirectly alter ovarian steroidogenesis (see below).…”

Soybean products and reduction of breast cancer risk: a case–control study in Japan

“…(1) increase of serum levels of sex hormone-binding globulin (SHBG) (Adlercreutz et al, 1991;Mousavi and Adlercreutz, 1993); (2) downregulation of enzymes involved in oestrogen biosynthesis, such as aromatase ; (3) inhibition of 17b-hydroxysteroid dehydrogenase type I (Makela et al, 1995); (4) suppression of the gonadotorpins follicule stimulating hormone (FSH) and luteinising hormone (LH); (5) change in intestinal flora, which affect reabsorption of E2 and lower circulating oestrogen levels (Adlercreutz, 1998). Studies examining the effect of a soy protein diet on the menstrual cycle have demonstrated a significant increase in follicular phase length and delay in menstruation, including suppression of midcycle surges of LH and FSH, which potentially may reduce the risk of breast cancer (Cassidy et al, 1994;Lu et al, 1996;Nagata et al, 1998;Kumar et al, 2002).…”