Dietary Phytoestrogens: Potential Selective Estrogen Jean-Philippe Basly1 Marie-Chantal Canivenc Lavier2 Enzyme Modulators? Review Abstract phytoestrogens, this contribution covers the estrogen pathway inhibition effects of these compounds and special attention will Between one-third to one-half of all breast cancers are steroid be given to isoflavonoids, flavonoids and lignans. Furthermore, sensitive. Steroid-pathway enzymes (sulfatase, 17b-hydroxyster- the research on structurally-related compounds as therapeutic oid dehydrogenases, aromatase and sulfotransferases) are thus agents will be discussed briefly. prime candidates for therapeutic approaches based on the con- trol of intacrine activity. Some phytoestrogens, ubiquitous in Key words our diet, are inhibitors of these enzymes. Such a therapeutic po- Phytoestrogens ´ aromatase ´ hydroxysteroid dehydrogenases ´ tential has stimulated research and progress has been achieved sulfatase ´ sulfotransferases ´ endocrine disrupters during the last years. Complementary to previous reviews on Introduction ªaromatase pathwayº which respectively transforms androste- nedione (AD) to estrone (E1) and testosterone (T) to estradiol Over the past 15 years, there has been a tremendous increase in (E2) and (ii) the ªsulfatase pathwayº which converts estrone sul- 287 the number of papers published on the biological activities of fate (E1S) into estrone (E1); estrone is then transformed into es- phytoestrogens. The estrogen receptor binding is the best-docu- tradiol (E2)by17b-hydroxysteroid dehydrogenase type 1. By ana- mented biological action of phytoestrogens and, as estrogen ago- logy with a selected estrogen receptor modulator (SERM), the nists and antagonists, they can be classified as selective estrogen concept of a selective estrogen enzyme modulator (SEEM) as a receptor modulators (SERMs) [1]. These compounds also have a therapeutic agent has recently emerged [3], [4]. The SEEMcan diverse range of other biological effects including the potential control the enzymatic mechanisms involved in the formation to alter the biosynthesis of endogenous hormones through a and transformation of estrogens (Fig.1). number of pathways. This contribution covers the inhibition of estrogen pathways by The high incidence of breast cancer in post-menopausal women phytoestrogens. In this way, previous reviews will be comple- and the lack of any correlation between the estrogen levels in mented [5], [6], [7]. plasma and the growth of breast cancer suggest that local estro- gen synthesis plays an important role in the pathogenesis of es- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. trogen-dependent breast cancer [2]. Two principal pathways are involved in the last steps of formation of 17b-estradiol: (i) the Affiliation 1 FacultØ de Pharmacie, UniversitØ de Limoges, Limoges, France. 2 UMR 1234, Toxicologie Alimentaire, INRA, Dijon, France Correspondence Dr. Jean-Philippe Basly ´ FacultØ de Pharmacie ´ UniversitØ de Limoges ´ 2 rue du docteur Marcland ´ 87025 Limoges ´ France ´ Phone/Fax: +33-555-43-58-98 ´ E-mail: [email protected] Received July 14, 2004 ´ Accepted January 7, 2005 Bibliography Planta Med 2005; 71: 287±294 ´ Georg Thieme Verlag KG Stuttgart ´ New York DOI 10.1055/s-2005-864092 ISSN 0032-0943 Fig. 1 Enzymatic bene), produced by plants as a defence mechanism against steps involved in the Botrytis cinerea has been identified as the major active com- synthesis of estro- pound and most of the studies about estrogenic/antiestrogenic genic steroids: the concept of selective activity have focused on it [7], [14]. estrogen enzyme modulator (SEEM; Current research is focusing on a number of lignans recently from Refs. [3] and identified in humans and several animals. Lignans are widely [4]). 17b-HSD-1 = distributed throughout the plant kingdom, where they are in- 17b-hydroxysteroid dehydrogenase type volved in plant defences, and the major sources are the outer lay- 1. SEEM-I inhibits er of cereals, mainly rye and flaxseed. They are converted into ac- the estrone sulfa- tive phytoestrogens called ªmammalian enterolignansº by the tase; SEEM-II inhi- proximal colon microflora [15]. Both trans-2,3-bis(3-hydroxy- bits the 17b-HSD-1; SEEM-III inhibits the aromatase activities; and benzyl)-g-butyrolactone and 2,3-bis(3-hydroxybenzyl)-butane- SEEM-IV stimulates the estrone sulfotransferase activity. T: testoster- Review 1,4-diol, known respectively as enterodiol (25) and enterolactone one; AND: androstenedione; E1: estrone; E2: estradiol; E1S: estrone sul- fate. (26) have been described as the major lignans. Lignans are close- ly related to phenolic estrogens and may function as weak estro- gens or estrogen antagonists [16]. Phytoestrogens: General Aspects Dietary phytoestrogens are defined as natural chemicals present SEEM 1: Sulfatase Inhibitors in our diet that can mimic or modulate the action of endogenous estrogens, usually by binding to estrogen receptors [6], [7]. Based Sulfatases are a group of hydrolytic enzymes that catalyse the con- on their chemical structure, phytoestrogens can be classified into version of various sulfated compounds to their corresponding un- four main groups, i.e., isoflavonoids, flavonoids, stilbenes and conjugated derivatives [17]. Desulfation of estrone sulfate by es- lignans (Fig. 2). To be complete, as mentioned recently by Cos trone sulfatase (SEEM 1) represents an important step in the [7], some terpenoids and saponins have been reported to exert transformation of inactive steroids to estrogenic hormones. Quan- similar effects. titative determinations in breast cancer tissues indicate that the ªestrone sulfatase pathwayº is about 130 ± 200-fold more impor- Isoflavones, found in Leguminosae (soybeans in particular) con- tant than the aromatase pathway [3]. Inhibition by isoflavone me- stitute the largest group of natural isoflavonoids. In this subclass, tabolites has been recently reported [18]. The most potent inhibi- the most thoroughly investigated and interesting compounds are tor was daidzein 7,4¢-bisulfate (7) which exhibited an IC50 value of genistein (1), daidzein (2), biochanin A (3) and formonetin (4). 0.8 mM. Daidzein 7-O-sulfate (5), daidzein 4¢-O-sulfate (6)and 288 Coumestans represent a fully oxidized version of pterocarpans genistein 7-O-sulfate (8) inhibited sulfatase activity with IC50 val- and are included in the isoflavonoids classification. The most ues < 20 mM. These results are quite similar to values previously representative, coumestrol (10), has been isolated from a few reported by Wong and Keung [19]. It seems that, since less than fodder and pasture plants (e. g., clover, alfalfa) belonging to the 0.1% of the conjugation products of isoflavones in humans are bi- Leguminosae. Estrogenic activities of isoflavonoids have been sulfates [20], concentrations of daidzein 4¢,7-bisulfate, even in widely studied [8], [9], [10], [11] and coumestrol is the phytoes- those consuming high soy/isoflavone-supplemented diets, would trogen that has the higher binding affinity for the estrogen recep- not be sufficient to influence sulfatase activity in vivo [18]. tors [9], [11]. None of the unconjugated flavonoids and isoflavonoids tested by Over 4000 flavonoids have been identified in plant sources. They Harris were found to have any effect on sulfatase (IC50 >25mM) are usually subdivided into flavonols (found throughout the at concentrations likely to be achieved from the diet. This con- plant foods), flavanols (catechins, epicatechins, gallocatechins, clusion is the opposite to Huang's paper where it was reported This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. epigallocatechins), anthocyanidins, chalcones, flavanones and that kaempferol (11), quercetin (12) and naringenin (16) act sig- flavones. Chalcones, flavanones (citrus fruits) and flavones (spi- nificantly as estrone sulfatase inhibitors [21]. ces and herbs) are described as minor flavonoids in spite of sometimes being present in food at a dietary significant concen- tration. Recent studies on the estrogenic activity of flavonoids in SEEM 2:17b-Hydroxysteroid Dehydrogenase vitro revealed that the estrogenic potency of flavonoids is 10±2 to 10 ±5-fold less than that of estradiol. However, 8-prenylnaringen- The 17b-hydroxysteroid dehydrogenases (SEEM 2), key enzymes in (20), a recently discovered flavanone from hops and beer, acting at the last step of androgen and estrogen formation, are demonstrated a higher estrogenic activity than coumestrol or nicotinamide adenine dinucleotide [NAD(H)]- and/or its phos- isoflavones [12], [13]. phate form [NADP(H)]-dependent enzymes that catalyse the oxi- dation and reduction of 17b-hydroxy and 17-ketosteroids in a po- Stilbenes are 1,2-diarylethenes detected in relatively few plant sitional and stereospecific manner [22]. 17b-HSD1 is expressed families where they contribute to the resistance to microbial de- in steroidogenic tissues including estrogen target tissues such gradation and act as phytoalexins. The major dietary sources of as normal and malignant breast tissues [23] and is a prognostic stilbenes are grapes, grape juices, wine and peanuts. Among marker in breast cancer [24]. It catalyses predominantly the con- monomeric stilbenes, resveratrol (24) (3,5,4¢-trihydroxystil- version of estrone to estradiol and can be considered to be pri- Basly J-P, Lavier M-CC. Dietary Phytoestrogens: Potential ¼ Planta Med 2005; 71: 287±294 Fig. 2 Chemical