3542 Current Medicinal Chemistry, 2010, 17, 3542-3574 0929-8673/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd. Hormonal Action of Plant Derived and Anthropogenic Non-Steroidal Estrogenic Compounds: Phytoestrogens and Xenoestrogens T. Lóránd 1 , É. Vigh 2 and J. Garai* ,2 1 Department of Biochemistry and Medical Chemistry, University of Pécs, Medical School, Pécs, Hungary 2 Department of Pathophysiology and Gerontology, University of Pécs, Medical School, Pécs, Hungary Abstract: Herbivorous and omnivorous vertebrates have evolved in the presence of a variety of phytoestrogens, i.e., plant-derived compounds that can mimic, modulate or disrupt the actions of endogenous estrogens. Since the discovery of the estrus-inducing effects of some plant products in 1926, considerable effort has been devoted to the isolation and struc- tural and pharmacological characterization of phytoestrogens. Recently, agricultural and industrial pollution has added an- thropogenic estrogenic compounds to the list of environmental estrogens. Unlike phytoestrogens, these xenoestrogens tend to accumulate and persist in adipose tissue for decades and may cause long-lasting, adverse endocrine effects. Here we review the endocrine effects of known phytoestrogens and xenoestrogens with special emphasis on molecular structure-activity relationships. Phytoestrogens include flavonoids, isoflavonoids, chalcons, coumestans, stilbenes, lig- nans, ginsenosides and other saponins, as well as the recently discovered tetrahydrofurandiols. Fungal estrogenic com- pounds may enter the food chain via infested crops. Since some phytoestrogens have been shown to display organ-specific actions, pharmaceutical estrogen analogues with similar properties (selective estrogen receptor modulators, SERMs) are also discussed. Xenoestrogens include dichlorodiphenyltrichloroethane (DDT) and its metabolites, bisphenols, alkylphe- nols, dichlorophenols, methoxychlor, chlordecone, polychlorinated biphenyls (PCBs), and dioxins. While most of these compounds act through estrogen receptors alpha and beta, some of their effects may be mediated by other nuclear or membrane-bound receptors or receptor-independent mechanisms. Some might also interfere with the production and me- tabolism of ovarian estrogens. Better understanding of the molecular pharmacology of phyto- and xenoestrogens may result in the development of novel compounds with therapeutic utility and improved environmental protection. Keywords: phytoestrogen, polyphenols, xenoestrogen, endocrine disruptors, persistent organic pollutants, estrogen receptors, SERM. 1. INTRODUCTION 1.1. Definition of Endocrine Disruption The first scientifically documented instance of the phe- nomenon currently known as endocrine disruption (ED) was the reproductive failure of certain Australian ewe popula- tions caused by the consumption of plant chemicals, which were later demonstrated to have the ability to interfere with the actions of ovarian estrogens [1]. A particular strain (Dwalganup) of subterranean clover (Trifolium subterra- neum) was found responsible, hence the name “clover dis- ease”. Several definitions are in use for endocrine disruptor chemicals (EDC). According to the International Programme on Chemical Safety (IPCS) “endocrine disruptor chemical could be an exogenous substance or mixture of them that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations” [2]. In contrast, the U.S. Envi- ronmental Protection Agency (EPA) defines EDC as “an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action, or elimination of natu- ral blood-borne hormones that are present in the body and *Address correspondence to this author at the Department of Pathophysiol- ogy and Gerontology, University of Pécs, Medical School Hungary, H-7624 Pécs, Szigeti u. 12, Hungary; Tel: +36 (72) 536-246; Fax: +36 (72) 536-247; E-mail: janos.garai@aok.pte.hu are responsible for homeostasis, reproduction, and develop- mental process” [3]. While the former approach aims to be more comprehensive, the latter focuses more on the particu- lar mechanisms involved. In this review we discuss the structure–activity relation- ships of plant-derived and anthropogenic environmental es- trogens, i.e., the largest and still expanding classes of EDCs. In addition, pharmaceutical estrogen analogues belonging to the class of selective estrogen receptor modulators (SERMs) are also included for comparative purposes. 1.2. Definition and Historical Aspects on Phytoestrogens The term “environmental estrogen” is currently used to cover both plant-derived estrogens (phytoestrogens) and the anthropogenic estrogens (xenoestrogens). While the term environmental estrogen is certainly correct from a bio- ecological point of view, it is too broad and impractical from a public health perspective. Although representatives of both groups are indeed found in the environment, clear distinction must be made between these groups when assessing the risks they might pose to human and wildlife health. Unlike xeno- estrogens, which have only recently entered the environment as a result of human activity, phytoestrogens have been pre- sent in the biosphere of Earth throughout the evolution of animal species including our own and must, therefore, be considered an integral part of our natural environment. How- ever, from an anthropocentric point-of-view, naturally pro-