The influence of dietary sunflower honey, propolis, and a flavonoid extract of propolis was examined on drug-metabolizing enzyme activities in rat liver and on microsome-mediated binding of benzo[a]pyrene to DNA. Characterization of flavonoids present in sunflower honey and propolis was achieved in order to assess the relative effects of different components of honey and propolis. Honey and propolis contained the same major flavonoids, pinocembrin, chrysin, galangin, and pinobanksin. The concentration of flavonoids was higher in propolis. Sunflower honey produced no significant changes on phase I and phase II enzyme activities and no modification of in vitro binding of benzo[a]pyrene to DNA. Propolis treatment produced an increase of ethoxyresorufin deethylase, pentoxyresorufin depentylase, ethoxycoumarin deethylase, glutathione transferase, and epoxide hydrolase activities. A flavonoid extract from propolis slightly enhanced only few enzyme activities, ethoxycoumarin deethylase and epoxide hydrolase. The induction pattern was similar to that observed with pinocembrin (a major flavonoid of propolis) administered solely. Binding of benzo[a]pyrene to DNA by microsomes from rats fed with propolis or a flavonoid extract from propolis was not significantly modified. These results contribute to identification of food or foodstuffs that can modify drug-metabolizing enzymes and binding of carcinogens to DNA. Keywords: Sunflower honey; propolis; flavonoids; drug-metabolizing enzymes; benzo[a]pyrene−DNA binding

IntroductionOver the past 15 years, there has been a tremendous increase in the number of papers published on the biological activities of phytoestrogens. The estrogen receptor binding is the best-documented biological action of phytoestrogens and, as estrogen agonists and antagonists, they can be classified as selective estrogen receptor modulators (SERMs) [1]. These compounds also have a diverse range of other biological effects including the potential to alter the biosynthesis of endogenous hormones through a number of pathways.The high incidence of breast cancer in post-menopausal women and the lack of any correlation between the estrogen levels in plasma and the growth of breast cancer suggest that local estrogen synthesis plays an important role in the pathogenesis of estrogen-dependent breast cancer [2]. Two principal pathways are involved in the last steps of formation of 17b-estradiol: (i) the ªaromatase pathwayº which respectively transforms androstenedione (AD) to estrone (E 1 ) and testosterone (T) to estradiol (E 2 ) and (ii) the ªsulfatase pathwayº which converts estrone sulfate (E 1 S) into estrone (E 1 ); estrone is then transformed into estradiol (E 2 ) by 17b-hydroxysteroid dehydrogenase type 1. By analogy with a selected estrogen receptor modulator (SERM), the concept of a selective estrogen enzyme modulator (SEEM) as a therapeutic agent has recently emerged [3], [4]. The SEEM can control the enzymatic mechanisms involved in the formation and transformation of estrogens (Fig. 1).This contribution covers the inhibition of estrogen pathways by phytoestrogens. In this way, previous reviews will be complemented [5] AbstractBetween one-third to one-half of all breast cancers are steroid sensitive. Steroid-pathway enzymes (sulfatase, 17b-hydroxysteroid dehydrogenases, aromatase and sulfotransferases) are thus prime candidates for therapeutic approaches based on the control of intacrine activity. Some phytoestrogens, ubiquitous in our diet, are inhibitors of these enzymes. Such a therapeutic potential has stimulated research and progress has been achieved during the last years. Complementary to previous reviews on phytoestrogens, this contribution covers the estrogen pathway inhibition effects of these compounds and special attention will be given to isoflavonoids, flavonoids and lignans. Furthermore, the research on structurally-related compounds as therapeutic agents will be discussed briefly.

Bisphenol A (BPA) is a widespread endocrine disrupting chemical (EDC) strongly suspected to have adverse health effects. Numerous tissues and cells are affected by BPA, and we showed recently that BPA targets include ameloblasts and enamel. We therefore investigated the effects of BPA on ameloblasts and the possible involvement of the estrogen signaling pathway. Rats were exposed daily to low-dose BPA, and developed enamel hypomineralization similar to human molar incisor hypomineralization (MIH). BPA increased ameloblast proliferation in vivo and in vitro. The proliferation of the rat dental epithelial cell line HAT-7 was also increased by estrogen (E2). Ameloblasts express ERα but not ERβ both in vivo and in vitro. The ER antagonist ICI 182,780 was used to inactivate ERα and abolished the effects of E2 on cell proliferation and transcription, but only partially reduced the effects of BPA. In conclusion, we show, for the first time, that: 1) BPA has ER-dependent and ER-independent effects on ameloblast proliferation and gene transcription; 2) the estrogen signaling pathway is involved in tooth development and the enamel mineralization process; and 3) BPA impacts preferentially amelogenesis in male rats. These results are consistent with the steroid hormones having effect on ameloblasts, raising the issues of the hormonal influence on amelogenesis and possible differences in enamel quality between sexes.