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  1. #1
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    Resveratrol and aromatase

    J. Agric. Food Chem., 54 (10), 3535 -3540, 2006. 10.1021/jf053237t S0021-8561(05)03237-1
    Web Release Date: April 22, 2006


    Modulation of Aromatase Activity by Diet Polyphenolic Compounds

    Rosrio Monteiro,* Isabel Azevedo, and Conceicao Calhau

    Introduction
    Estrogens influence several physiological processes both in males and females. The most obvious and best known of their actions is the regulation of reproductive functions. But estrogens have other not so obvious but also important activities. The more favorable conditions for cardiovascular health found in premenopausal women in comparison to men have been partially attributed to estrogens (1). There is also a clear involvement of these hormones in the formation and maintenance of bone in later life (2). Estrogen involvement in determining the amount and distribution of body fat (3) can also largely influence health, since obesity, especially the visceral type, influences the risk for cardiovascular diseases and diabetes (4). Additionally, estrogens have neuroprotective actions (2). On the other hand, estrogens have a profound impact in the development of estrogen-dependent cancers such as breast and prostate cancer (5). Concerning breast cancer, it is currently known that approximately 60% of premenopausal and 75% of postmenopausal breast cancer patients have estrogen-dependent tumors (6). Therapeutic approaches to these conditions may include one of two strategies to impair estrogen action: either blockade of the action of estrogens through estrogen receptor (ER) antagonists (or antiestrogens) or inhibition of their synthesis using modulators of aromatase activity (7).

    Aromatase (EC.1.14.13) is a cytochrome P450 (CYP) enzyme that catalyses the aromatization of androgens (testosterone and androstenedione) to estrogens (estradiol and estrone, respectively) by three consecutive hydroxylation steps (8). It is most abundant in the ovary and placenta but exists also in other organs and tissues such as the brain and adipose tissue (8).

    Polyphenols are a wide group of molecules present in almost all plant-based foods. Some classes of polyphenols have structural similarities to estrogens, being good candidates for a possible interference with estrogen-regulated cellular events (9).

    Polyphenols of various food sources are being increasingly related to health, including inhibition of cancer initiation, promotion, and progression (10). Much interest has focused on wine and tea, polyphenolic-rich beverages, which are presently being recognized in epidemiological and experimental studies as possessing chemopreventive properties (11-14). Reduction of oxidative stress (13-15), angiogenesis inhibition (16), impairment of procarcinogen activation (14, 15), and regulation of the cell cycle (11, 17) are among the most common mechanisms attributed to these beverages that may explain their anticarcinogenic effects. However, little is known about their ability to interfere with estrogen synthesis (17-22).

    The purpose of this work was to study the effect of polyphenolic compounds on estrogen synthesis. The effect of beverages rich in these polyphenolic compounds was also investigated. Choriocarcinoma-derived JAR cells were used to determine aromatase activity by tritiated water release assay. Because JAR cells express high levels of this enzyme, they are considered a good model for its investigation (23-25).

    Materials and Methods
    [Omitted to save space - will produce upon request]

    Results
    Phenolic Compounds. Tested compounds included a flavone (chrysin), a flavanone (naringenin), isoflavones (daidzein and genistein), flavonols (kaempferol, myricetin, quercetin, and rutin), flavanols (catechin, epicatechin, and epigallocatechin-3-gallate), and a stilbene (resveratrol) (Figure 1). After 3 h in contact with JAR cells, all these compounds inhibited aromatase activity. To compare inhibitory strength, cells were incubated with different concentrations of these compounds, and the concentration required for 50% inhibition of aromatase activity (IC50) was determined. Chrysin, naringenin, and quercetin were the most potent polyphenols in inhibiting aromatase activity (Table 1). Kaempferol, myricetin, and [u]resveratrol did also markedly inhibit aromatase, while epigallocatechin-3-gallate had a less-pronounced effect, with an IC50 of 1770 (1501-2088) mol/L (Table 1). For catechin, epicatechin, genistein, and rutin it was not possible to assess the IC50; therefore, the maximal aromatase activity reduction (% of control) was determined. Catechin (1 mmol/L), epicatechin (2 mmol/L), genistein (1 mmol/L), and rutin (1 mmol/L) reduced aromatase activity by 31, 40, 26, and 23%, respectively (Table 2). None of the tested compounds interfered with cell viability (results not shown). Concerning aromatase expression as determined by western blotting and RT-PCR, no effect of any of the polyphenols was found after treatment of JAR cells with the compounds for 24 h (results not shown).


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    Figure 1 Chemical structure of the polyphenols tested: (A) catechin, (B) chrysin, (C) daidzein, (D) epicatechin, (E) epigallocatechin-3-gallate, (F) genistein, (G) kaempferol, (H) myricetin, (I) naringenin, (J) quercetin, (K) resveratrol, and (L) rutin.

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    Figure 2 Effect of beverages on aromatase activity. (A) Wine (n = 6; C, no treatment; C', 12% (v/v) ethanol control; RW, red wine; WW, white wine). *P < 0.05 vs C, C', and WW. (B) Alcohol-free beverages (n = 6; C, no treatment; C', 0.9% NaCl (w/v) control; AF-RW, alcohol-free red wine; AF-WW, alcohol-free white wine; GT, green tea; BT, black tea). *P < 0.05 vs C and C'. Confluent JAR monolayers were preincubated at 37 C for 2 h and then incubated for 1 h in the presence of 200 L/mL of beverages (or vehicle). The incubation was carried out with 54 nM [3H]androstenedione, at 37 C. Results represent means ? SEM.

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  2. #2
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    Discussion
    It is no longer a matter of debate that food habits largely influence biological events with strong repercussion in individual health. For example, the Mediterranean diet, which has been the subject of scientific interest for the past few years, is believed to result in lower incidence of cancer and cardiovascular diseases (28, 29).

    A feature that makes this such a special kind of diet is its high levels of polyphenols. Wine and tea are polyphenol-rich beverages which have been reported to possess cancer-preventive activity. Some of the mechanisms by which this effect occurs have already been elucidated and include antioxidant, antiinflamatory, antimutagenic, antiangiogenic, antiestrogenic, and cell cycle regulating actions (10, 13, 16).

    Thus, we considered it to be of interest to know which kind of effect diet polyphenols would have on estrogen synthesis. To do so, JAR cells were incubated with increasing concentrations of selected polyphenols and the IC50 was determined for each compound.

    Most of the polyphenols tested could inhibit aromatase, chrysin, naringenin, quercetin, kaempferol, myricetin, and resveratrol showing the strongest inhibitory ability. Although chrysin, the most potent inhibitor of aromatase activity, with an IC50 of around 6 M, has not yet been identified in any of the beverages tested here, it is present in foodstuffs that are part of human diet (30). Naringenin, which is especially abundant in citrus fruits, but can be found in small amounts in red wine (RW), was also found to be a good inhibitor of aromatase. These results are in agreement with what has been described by others (31-33).

    Flavonols quercetin, kaempferol, myricetin, and rutin may also be found in wine and tea (13, 34). The first three produced a strong reduction, while the latter had almost no effect on aromatase activity. Because rutin is a rhamnoside of quercetin, its crossing of the plasma membrane depends on the hydrolysis of the sugar moiety by -glucosidases (35) which do not exist in JAR cells. Other authors have also found no effect of 100 mol/L of rutin on aromatase activity (19).

    Catechins are the most abundant polyphenols found in all three types of beverages tested. Catechin and epicatechin are mainly present in wine (34), and epigallocatechin-3-gallate is more abundant in tea, especially in GT (13). Satoh et al. (22) found that epigallogatechin-3-gallate reduced aromatase activity in placental microsomes with an IC50 of 60 mol/L (vs 1770 mol/L found in this study). The fact that, in our experimental model, this compound has to cross the plasma membrane to penetrate the cell may explain the differences of potency between our and other results.

    Genistein and daidzein are isoflavones and had previously been described as having a poor aromatase inhibitory ability (33), which is corroborated by our results. In fact, daidzein produced no inhibition of aromatase when tested up to 1 mmol/L. Genistein (1 mmol/L) reduced aromatase activity only slightly, to 74% of that of the control.

    Some of these compounds possess aromatase inhibitory activity in concentrations above the levels found after the ingestion of polyphenol-rich usual sources. However, the results show the possibility of compounds from plant-based foods to interfere with estrogen synthesis. Even if not of interest for nutritional reasons, the pharmacological interest is indisputable.

    As expected from the results obtained in the presence of polyphenol compounds, the present work showed that RW and tea inhibited aromatase activity in JAR cells.

    Wine is produced from the fermentation of grapes of the species Vitis vinifera. During this process grape skins and seeds are kept in contact with growing ethanol concentrations for longer or shorter periods of time, in the production of RW or WW, respectively. This will largely determine the polyphenolic content of the wine (more than 1000 mg/L in RW and less than 50 mg/L in WW) (34). The incubation of JAR cells with RW resulted in strong inhibition of aromatase, as opposite to WW, which had no effect on this enzyme. This difference suggests that polyphenols may be involved in aromatase modulation.

    In using the beverages in direct contact with the cells, we have tried to maintain the original properties of the beverage. With the manipulation of the wine matrix, fractionating or evaporating and reconstituting the beverages, we could possibly lose compounds or the interaction between them.

    Aromatase catalyses a critical step for estrogen production from circulating androgens (8). Estrogens have a role in estrogen-dependent cancers such as some endometrium and breast cancers (6, 35), and estrogen synthesis blockade has unquestionable value as a therapeutic approach in breast cancer management (36).


    When tested alone, ethanol, the main ethanol present in wines, was able to significantly decrease aromatase activity. However, as just shown, the effect of the beverages with and without ethanol on aromatase activity was the same.

    GT is the beverage prepared by the infusion of dry leaves of Camellia sinensis, which is also rich in polyphenols. For the production of BT, leaves are allowed to oxidize prior to drying, which results in the production of new compounds (13). There have been several studies concerning GT and BT's ability to reduce the genesis of estrogen-dependent or -independent cancers such as ovarian and skin cancer (38, 39). In the present study, GT and BT did significantly inhibit aromatase, and this may have impact on the development of breast cancer.

    Thus, the results obtained in the presence of polyphenolic compounds may partially account for the inhibition of aromatase activity observed in the presence of wine and tea. However, it is important to bear in mind that these beverages are complex mixtures of polyphenols and other compounds may contribute to their effect. The occurrence of additive/synergistic effects is also possible.

    Despite their effects on aromatase activity, when the same polyphenols were tested for 24 h in JAR cells, no effect on aromatase expression was observed. Thus, the modulation of aromatase activity by polyphenols might be due to their interaction with the enzyme or with the metabolic pathways regulating its activity, without effects on the expression of the CYP19 gene. In fact, it has been suggested that polyphenolic rings A and C mimic aromatase substrate rings C and D, being thus able to inhibit aromatase (Figure 3) (40). Curiously, in our study, the compounds with the strongest inhibitory effects possessed a carbonyl group on the C4 of ring C. This feature may be relevant for the interaction of polyphenols with aromatase. The disturbance of the CYP catalytic cycle is also possible, since polyphenols are antioxidant molecules that may either reduce NADPH or O2 availability, decreasing the possibility of the aromatase reaction to proceed. This is supported by the fact that some of the tested beverages, or their compounds, are able to inhibit other CYP isoenzymes, as demonstrated for RW (41, 42), tea (15), and resveratrol (42, 43).


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    Figure 3 Structural homology between the aromatase substrate (A) and the basic flavonoid structure (B).

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    Although detailed knowledge on polyphenol bioavailability is still lacking, there is evidence that after consumption of polyphenol-rich foods or beverages these compounds appear in plasma in concentrations varying with the polyphenol in question and the amount ingested (43). Although in this study some of the polyphenols showed aromatase-inhibiting activities in concentrations far above those present in plasma after consumption of a single serving of drink, one should not discard the possibility of those plasma levels being higher after the simultaneous ingestion of polyphenols from several sources. Furthermore, once several compounds have been shown to be able to inhibit aromatase, it is possible that these molecules exert additive effects, producing a measurable and significant reduction of estrogen synthesis in vivo.

    In conclusion, RW and tea are able to modulate aromatase activity, which may, at least in part, be explained by the polyphenols contained in these beverages. The interference of these products with estrogen synthesis may make them interesting for the prevention/treatment of estrogen-dependent disorders such as breast cancer.

    Abbreviations Used
    AF, alcohol-free; BT, black tea; CYP, cytochrome P450; DEPC, diethyl pyrocarbonate; ER, estrogen receptor; GAPDH, glyceraldehyde phosphate dehydrogenase; GT, green tea; LDH, lactate dehydrogenase; NADPH, nicotinamide-adenine dinucleotide (reduced form); RW, red wine; WW, white wine.

    Acknowledgment
    We gratefully acknowledge the preparation of alcohol-free wines to Professor Paula Guedes de Pinho from ESBUC. We also thank the excellent support of Eng Jose Machado Cruz from Instituto de Bebidas e Saude.


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  3. #3
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    Interesting. This certainly puts one company's claims regarding its product in doubt.
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