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Endocrinology Vol. 140, No. 1 50-54
Copyright © 1999 by The Endocrine Society

ARTICLES

Is Resveratrol an Estrogen Agonist in Growing Rats?1

Russell T. Turner, Glenda L. Evans, Minzhi Zhang, Avudaiappan Maran and Jean D. Sibonga

Departments of Orthopedics, Biochemistry, and Molecular Biology, Mayo Graduate School of Medicine, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Russell T. Turner, Ph.D., Orthopedic Research, Room 3–69 Medical Science Building, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Trans-3,4,5-trihydroxystilbene (resveratrol), a polyphenolic compound found in juice and wine from dark-skinned grape cultivars, was recently shown to bind to estrogen receptors in vitro, where it activated transcription of estrogen-responsive reporter genes. The purpose of this 6-day study in weanling rats was to determine the dose response (1, 4, 10, 40, and 100 µg/day) effects of orally administered resveratrol on estrogen target tissues. The solvent (10% ethanol) had no significant effect on any measurement or derived value. 17ß-Estradiol treatment (100 µg/day) decreased the growth rate, final body weight, serum cholesterol, and radial bone growth (periosteal bone formation and mineral apposition rates) at the tibia-fibula synostosis. In the uterus, 17ß-estradiol treatment increased wet weight, epithelial cell height, and steady state messenger RNA levels for insulin-like growth factor I. In contrast, resveratrol treatment had no significant effect on body weight, serum cholesterol, radial bone growth, epithelial cell height, or messenger RNA levels for insulin-like growth factor I. Resveratrol treatment resulted in slight increases in uterine wet weight, but significance was achieved at the 10-µg dose only. A second experiment was performed to determine whether a high dose of resveratrol (1000 µg/day) antagonizes the ability of estrogen to lower serum cholesterol. As was shown for the lower doses, resveratrol had no effect on body weight, uterine wet weight, uterine epithelial cell height, cortical bone histomorphometry, or serum cholesterol. 17ß-Estradiol significantly lowered serum cholesterol, and this response was antagonized by cotreatment with resveratrol. These in vivo results suggest, in contrast to prior in vitro studies, that resveratrol has little or no estrogen agonism on reproductive and nonreproductive estrogen target tissues and may be an estrogen antagonist.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
TRANS-RESVERATROL (resveratrol) is a polyphenolic compound that is found in fresh grapes, grape juice, and wine. Resveratrol is localized in the grape skin; its concentration varies with specific grape cultivar, climate, and viticultural practices (1, 2, 3). Higher concentrations of resveratrol are found in dark-skinned grapes than in light-skinned varieties (2). As a consequence of the differences between the varieties and methods of processing the grapes, red wines usually contain more resveratrol than white, rosé, or blush wines (2).

Resveratrol has been implicated in many (4, 5, 6, 7), but not all (8, 9), studies as a mediator of the alcohol-independent cardiovascular protection that is allegedly conferred by drinking red wine. Recently, resveratrol was shown to compete with 17ß-estradiol for estrogen receptors in vitro (10). Additionally, resveratrol activated transcription of estrogen-responsive reporter genes transfected into human breast cancer cells (10). The physiological significance of these findings are unknown because resveratrol has not yet been shown to have effects on estrogen target tissues in vivo. With this in mind, we now report the dose-response effects of resveratrol on representative reproductive and nonreproductive estrogen target tissues in weanling rats.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
These studies were approved by the Mayo Foundation institutional animal care and use committee.

Exp 1
This study was performed to determine whether resveratrol is an estrogen agonist on selected reproductive and nonreproductive estrogen target tissues. Forty-two weanling (3-week-old) female Sprague-Dawley rats were obtained from Harlan Sprague-Dawley, Inc. (Indianapolis, IN). The rats were weighed and randomly divided into eight groups, with five or six animals per group. The groups consisted of 1) untreated, 2) solvent treated, 3) estrogen treated (100 µg/day), and 4–8) resveratrol treated (1, 4, 10, 40, and 100 µg/day, respectively). Resveratrol (Sigma Chemical Co., St. Louis, MO) was dissolved in 95% ethanol and diluted with water. Part (0.5 ml) of the final 10% ethanol solution was administered to the rats once a day orally by gavage. 17ß-Estradiol was administered to the rats ip. For bone histomorphometry, the fluorochrome calcein (20 mg/kg; Sigma Chemical Co.) was administered by tail vein injection at the start of the experiment and 1 day before death. The rats were weighed and anesthetized with ketamine HCl (16.4 mg)-xylazine HCl (0.18 mg), and trunk blood was collected after decapitation.

After death, the uterus was quickly excised, freed of connective tissue, weighed, and frozen in liquid N2. The uteri were stored frozen at -84 C until RNA was isolated. The tibiae were excised and stored in 70% ethanol until they were processed for bone histomorphometry.

Exp 2
This study was performed to determine whether resveratrol antagonizes the ability of estrogen to lower serum cholesterol. Forty-two weanling Sprague-Dawley rats were obtained from Harlan Sprague-Dawley, Inc. The rats were weighed and randomly divided into eight groups, with five (treatment groups) or seven (solvent-treated control group) animals per group. The groups consisted of 1) solvent treated control, 2–4) 17ß-estradiol treated (1, 10, and 100 µg/day, respectively), 5) resveratrol treated (1000 µg/day), and 6–8) combination treatment with resveratrol (1000 µg/day) and 17ß-estradiol (1, 10, and 100 µg/day, respectively). The treatments were given daily by gavage as described in Exp 1. After 6 days of treatment the rats were killed and necropsied as described in Exp 1.

Mean growth rate
The mean growth rate was calculated as the difference between final weight and starting weight divided by 6 days.

Serum cholesterol
Serum cholesterol was determined by the Immunochemical Laboratory Core Facility at the Mayo Clinic using an automated procedure (Roche Diagnostic System, Los Angeles, CA). Cholesterol is released from its esters by the enzymatic action of an ester hydroxylase. Free cholesterol is then oxidized by cholesterol oxidase, producing hydrogen peroxide. The hydrogen peroxide, when combined with 4-amino-antipyrine and phenol, forms a chromophore in an amount that is directly proportional to the cholesterol concentration and is quantitated photometrically.

Histomorphometry
All measurements were performed with an Osteomeasure semi-automatic image analysis system (Osteomeasure, Atlanta, GA), which has been described in detail previously (11).

All cortical measurements were made on 20-µm-thick unstained, undemineralized ground sections as previously described (11). The primary static measurements consisted of cross-sectional area and medullary area. Cortical area was calculated as previously described (11). The primary dynamic measurements consisted of bone formed during the interval between administration of the sequential fluorochrome labels and labeled perimeter. The bone formation and mineral apposition rates were calculated from these data as previously described (11).

Uterine histology
Epithelial cell height was measured in 7-µm-thick microtome-cut sections of paraffin-embedded uterine tissue as previously described (12).

RNA analyses
Total cellular RNA was isolated from uteri as previously described (13). A ribonuclease (RNase) protection assay was used to measure steady state levels messenger RNA (mRNA) levels for insulin-like growth factor I (IGF-I) and L32. IGF-I is an important growth factor that is rapidly up-regulated by estrogen in the uterus. L32 is a ribosomal protein. The mRNA levels for IGF-I were normalized to L32 to correct for differences in the amounts of RNA that were hybridized with the probes. The assay was performed using the kit as recommended by the manufacturer (Ambion, Inc., Austin, TX). Antisense IGF-I RNA probe was synthesized using T3 RNA polymerase and a cloned fragment of IGF-I complementary DNA as previously described (14). L32 antisense RNA probe was synthesized using T7 RNA polymerase and complementary DNA fragment purchased from PharMingen (San Diego, CA). The purified antisense RNA probes of IGF-I and L-32 (3 x 106 cpm each) were hybridized with 20 µg total cellular RNA isolated from tissues for 18 h at 43 C as described by the manufacturer (Ambion, Inc.). The RNase-digested, protected fragments were separated on acrylamide-urea gels. Quantitation of protected IGF-I and L32 RNA fragments was performed by PhosphorImage analyses (Molecular Dynamics, Inc., Sunnyvale, CA). The sizes of the protected IGF-I and L32 mRNA fragments are 226 and 112 bp, respectively.

Statistical analysis
Measurements in which statistical significance was P < 0.05 by one-way ANOVA were tested by multiple comparisons using the Fisher protected least significant difference post-hoc test to establish group differences.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
General
The animals appeared healthy. The solvent (10% ethanol) had no effect on any measured or calculated value compared with that in untreated rats (data not shown).

Exp 1
Body weight. The weight data are shown in Table 1Go. All treatment groups grew during the 6-day experiment. Resveratrol had no effect on either final body weight or mean growth rate, with the exception of a small decrease in the calculated mean growth rate at the highest dose rate. These largely negative findings contrast with the pronounced inhibitory effect of estrogen treatment on the final body weight and mean growth rate.


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  		Table 1. The dose-response effects of resveratrol on body weight

 
Uterus. Uterine wet weight, epithelial cell height, and the steady state IGF-I mRNA level were measured (Fig. 1Go) to evaluate the dose-dependent effects of resveratrol on selected indexes of uterine growth and differentiation. A phosphoimage of a representative RNase protection assay for IGF-I is shown in Fig. 2Go. As expected, high levels of the mRNA for IGF-I were expressed in the uterus. None of the treatments had any effect on mRNA levels for ribosomal protein L32. 17ß-Estradiol increased uterine weight (Fig. 1AGo), epithelial cell height (Fig. 1BGo), and mRNA levels for IGF-I (Fig. 1CGo) compared with those in the solvent-treated controls. Resveratrol treatment resulted in a tendency toward slight increases in uterine wet weight, epithelial cell height, and mRNA levels for IGF-I. No dose response was observed, and with the exception of increased uterine weight at one dose (10 µg), statistical significance was not achieved.



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  		Figure 1. The dose-response effects of resveratrol on indexes of uterine growth and differentiation: A, uterine wet weight; B, epithelial cell height; and C, IGF-I mRNA levels. Values are the mean ± SE. *, P < 0.05 (µm); **, P < 0.01. C, Control; E, 17ß-estradiol. The indicated doses of resveratrol (R) are expressed as micrograms per day.

 


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  		Figure 2. Photographs of a representative phosphoimage of a RNase protection assay for IGF-I and L32 illustrating the lack of an effect of resveratrol on steady state mRNA levels for IGF-I. C, Control. The indicated doses of resveratrol (R) are expressed as micrograms per day. In contrast, 17ß-estradiol resulted in a large increase in steady state mRNA levels for IGF-I (assay not shown).

 
Serum cholesterol. Serum cholesterol is shown in Fig. 3Go. 17ß-Estradiol decreased serum cholesterol compared with that in age-matched controls, whereas resveratrol had no effect on serum cholesterol.



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  		Figure 3. The dose-response effects of resveratrol on serum cholesterol. Values are the mean ± SE. *, P < 0.05. C, Control; E, 17ß-estradiol. The indicated doses of resveratrol (R) are expressed as micrograms per day.

 
Cortical bone measurements. The static and dynamic cortical bone measurements are tabulated in Table 2Go. None of the treatments altered cross-sectional area, medullary area or cortical bone area. 17ß-Estradiol decreased the periosteal bone formation and mineralization rates compared with the controls. On the other hand, resveratrol had no effect on dynamic cortical bone measurements.


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  		Table 2. The dose-response effects of resveratrol on cortical bone histomorphometry

 
Exp 2
Resveratrol (1000 µg/day) had no significant effect on body weight, weight gain, uterine wet weight, uterine epithelial cell height, or cortical bone histomorphometry (data not shown). The effects of resveratrol, 17ß-estradiol, and combination treatment on serum cholesterol are shown in Fig. 4Go. Resveratrol treatment had no effect on serum cholesterol. Resveratrol antagonized the cholesterol-lowering activity of the two lower doses of 17ß-estradiol, but did not prevent the cholesterol-lowering activity of the highest dose.



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  		Figure 4. The dose-response effects of 17ß-estradiol with or without cotreatment with resveratrol. Values are the mean ± SE. *, P < 0.05; **, P < 0.01; ***, P < 0.001. C, Control. The indicated dose rates for 17ß-estradiol (E) and resveratrol (R) are expressed as micrograms per day.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our in vivo results demonstrate that resveratrol does not stimulate indexes of uterine growth and differentiation in immature rats; even very high doses of resveratrol generally had insignificant effects on uterine wet weight, epithelial cell height, and IGF-I gene expression. Additionally, resveratrol had no effect on other estrogen target tissues; treatment with resveratrol did not alter cortical bone growth, the serum concentration of cholesterol, or body weight. We conclude from these findings that resveratrol is not an estrogen agonist in the rat.

Resveratrol was shown by Gehm et al. (10) to bind to estrogen receptors and activate estrogen-responsive genes in vitro. It was suggested by these authors that the estrogenic actions of resveratrol may be relevant to the reported cardiovascular benefits of drinking wine (10). However, the weak IC50 for resveratrol binding to the estrogen receptor of approximately 10 µM and the weak EC50 for estrogenic stimulation of between 3 and 10 µm, depending on the test system examined, raise questions regarding the physiological significance of these in vitro findings.

The concentration of resveratrol in grapes, grape juice, and wine is highly variable. Also, grapes contain cis- as well as trans-resveratrol. Although the affinity of cis-resveratrol to the estrogen receptor has not been measured, it’s conformation leads one to suspect that the binding will be much weaker than the trans-isomer. The conversion of resveratrol to the cis-isomer is potentiated by heat and UV light and would probably reduce the potential estrogenic activity of this putative phytoestrogen (15, 16). Additionally, it is possible that resveratrol is metabolized to other products that differ from the parent compound in estrogenic activity. Importantly, only the lowest two dose rates used in the present study for administration of resveratrol fall within the range that a moderate wine drinker might ingest (1, 2, 3). This contrasts with the higher dose rates studied, which would greatly exceed dietary exposure to resveratrol.

Although we did not measure plasma or tissue levels of resveratrol, such measurements have been measured by Bertelli et al. (15, 16). Oral administration of 28 µg resveratrol in red wine to male rats resulted in peak plasma levels of resveratrol of greater than 20 ng/ml after 1 h. Importantly, resveratrol was shown to be bioavailable to several tissues, including heart, liver, and kidney, and was retained in these tissues.

Resveratrol is sparingly soluble in water. We administered resveratrol in a 10% ethanol solution to model wine. The daily intake of ethanol in this study ranged from 0.75–1.5 g/kg, which is equivalent to a 50-kg human consuming 3–6 glasses of wine. This quantity of ethanol is generally considered to exceed moderation (17). However, this volume of ethanol is often consumed by nonalcoholics, was essential to solubilize the highest dose rates of resveratrol, and had no significant effect on any measurement performed in this study.

The effects of 17ß-estradiol observed in this study were consistent with previous studies. As expected, the hormone stimulated indexes of uterine growth (wet weight) and differentiation (increased epithelial cell height and steady state IGF-I mRNA levels) and suppressed weight gain, serum cholesterol, and radial bone growth (18, 19, 20).

Resveratrol had minimal effects on uterine growth and differentiation. Although it is possible that higher concentrations of resveratrol might have more pronounced effects on the uterus, higher doses would not be relevant to the levels present in either grape juice or wine. Furthermore, the competition studies in which resveratrol antagonized the hypocholesterolemic response to estrogen suggest that resveratrol binding to estrogen receptors was achieved. This conclusion has been verified by studies in which we have shown that pretreatment with resveratrol (1000 µg) reduces by about 50% the accumulation of tracer levels of [3H]17ß-estradiol into nuclei of uteri from ovariectomized sexually mature rats (Sibonga, J., and R. T. Turner, unpublished results).

Resveratrol had variable effects on activation of estrogen-regulated genes in vitro; some were activated to a greater extent than with 17ß-estradiol, whereas others were activated to a lesser extent (10). These findings suggested that resveratrol might have tissue-selective actions analogous to triphenylethylene- and benzothiophene-selective estrogen receptor modulators (21). This possibility was not substantiated in the present studies. In contrast to the selective estrogen receptor modulators, resveratrol did not reduce serum concentrations of cholesterol, suppress weight gain, or antagonize radial bone growth.

Estrogen is believed to benefit the cardiovascular system in part by decreasing platelet aggregation and increasing serum low density lipoprotein cholesterol. The ED50 values for cholesterol lowering by partial estrogen agonists are highly correlated with binding affinity to the estrogen receptor (22). Furthermore, the potent estrogen antagonist ICI 182,780 increases total serum cholesterol (23). These findings provide strong support that the hypocholesterolemic activity of estrogen is through an estrogen receptor-mediated mechanism. The effects of resveratrol on platelet aggregation and cholesterol metabolism are controversial (4, 5, 6, 7, 8, 9). In the current studies in weanling rats, neither ethanol nor resveratrol altered total serum cholesterol. However, as 17ß-estradiol reduced total serum cholesterol (19, 23, 24) and resveratrol antagonized that activity, we can conclude that resveratrol is an estrogen antagonist on cholesterol metabolism.

Estrogen secretion at puberty is an important determinant of peak bone mass in rats (25). The inhibition of cortical bone growth in rats by estrogen is well established (18). Estrogen receptor mRNA has been identified in the periosteum (15), and the cascade induced by the hormone in this tissue (25) is antagonized by ICI 182,780 (23). The failure to detect an effect on bone histomorphometry implies that resveratrol is not an estrogen agonist on cortical bone.

We are uncertain whether there are species differences in either the absorption of resveratrol or the binding of resveratrol to estrogen receptors. However, resveratrol has been shown to be absorbed by rats (15, 16) and humans (8) after oral administration of red wine. Furthermore, we are not aware of any major differences between rats and humans in the relative binding of estrogen agonists to estrogen receptors.

Estrogen reduces weight gain in rats in part by decreasing food consumption. Pair feeding ovary-intact and ovariectomized rats is only partially effective in controlling the accumulation of adipose tissue, indicating that gonadal hormones also influence the utilization of calories (18). The lack of an effect on body weight suggests that resveratrol is not an estrogen agonist on this activity.

In summary, dose-response studies revealed that orally administered resveratrol had minimal in vivo effects on estrogen target tissues in rats, including no effect on uterine growth and differentiation, body weight, serum cholesterol, or radial bone growth. In contrast, resveratrol antagonized the effects of estrogen to lower serum cholesterol. We conclude that it is unlikely that the cardiovascular protective effects of moderate wine drinking are due to the binding and activation of estrogen receptors by resveratrol.


   Acknowledgments
 
The authors gratefully acknowledge the editorial assistance of Ms. Lori Rolbiecki.


   Footnotes
 
1 This work was supported by NIH Grant AA-11140 and the Mayo Foundation. Back

Received May 5, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Celotti E, Ferrarini R, Zironi R, Conte LS 1996 Resveratrol content of some wines obtained from dried Valpolicella grapes: recioto and Amarone. J Chromatogr [A] 730:47–52[CrossRef][Medline]
  2. Sato M, Suzuki Y, Okuda T, Yokotsuka K 1997 Contents of resveratrol, piceid, and their isomers in commercially available wines made from grapes cultivated in Japan. Biosci Biotechnol Biochem 61:1800–1805[Medline]
  3. Mattivi F 1993 Solid phase extraction of trans-resveratrol from wines for HPLC analysis. Z Lebensm Unters Forsch 196:522–525[CrossRef][Medline]
  4. Bertelli AAE, Giovannini L, Giannessi D, Migliori M, Bernini W, Fregoni M, Bertelli A 1995 Antiplatelet activity of synthetic and natural resveratrol in red wine. Int J Tissue React 17:1–3[Medline]
  5. Goldberg DM, Hahn SE, Parkes JG 1995 Beyond alcohol: beverage consumption and cardiovascular mortality. Clin Chim Acta 237:155–187[CrossRef][Medline]
  6. Pace-Asciak CR, Hahn S, Diamandis EP, Soleas G, Goldberg DM 1995 The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease. Clin Chim Acta 235:207–219[CrossRef][Medline]
  7. Pace-Asciak CR, Rounova O, Hahn SE, Diamandis EP, Goldberg DM 1996 Wines and grape juices as modulators of platelet aggregation in healthy human subjects. Clin Chim Acta 246:163–182[CrossRef][Medline]
  8. Goldberg DM, Garovic-Kocic V, Diamandis EP, Pace-Asciak CR 1996 Wine: does the colour count? Clin Chim Acta 246:183–193[CrossRef][Medline]
  9. Wilson T, Knight TJ, Beitz DC, Lewis DS, Engen RL 1996 Resveratrol promotes atherosclerosis in hypercholesterolemic rabbits. Life Sci 59:PL15–PL21
  10. Gehm BD, McAndrews JM, Chien P-Y, Jameson JL 1997 Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci USA 94:14138–14143[Abstract/Free Full Text]
  11. Jimenez MA, Magee DE, Bryant HU, Turner RT 1997 Clomiphene prevents cancellous bone loss from tibia of ovariectomized rats. Endocrinology 138:1794–1800[Abstract/Free Full Text]
  12. Westerlind KC, Gibson KJ, Malone P, Evans GL, Turner RT 1998 Differential effects of estrogen metabolites on bone and reproductive tissues of ovariectomized rats. J Bone Miner Res 13:1023–1031[CrossRef][Medline]
  13. Westerlind KC, Sarkar G, Bolander ME, Turner RT 1995 Estrogen receptor mRNA is expressed in vivo in rat calvarial periosteum. Steroids 60:484–487[Medline]
  14. Cavolina JM, Evans GL, Harris SA, Zhang M, Westerlind KC, Turner RT 1997 The effects of orbital spaceflight on bone histomorphometry and mRNA levels for bone matrix proteins and skeletal signaling peptides in ovariectomized growing rats. Endocrinology 138:1567–1576[Abstract/Free Full Text]
  15. Bertelli AAE, Giovannini L, Stradi R, Urien S, Tillement JP 1996 Kinetics of trans- and cis-resveratrol (3,41,5-trihydroxystilbene) after red wine oral administration in rats. Int J Clin Pharmacol Res 16:77–81[Medline]
  16. Bertelli AAE, Giovannini L, Stradi R, Bertelli A, Tillement J-P 1996 Plasma, urine and tissue levels of trans- and cis-resveratrol (3,4,5-trihydroxystilbene) after short-term or prolonged administration of red wine to rats. Int J Tissue React 18:67–71[Medline]
  17. Kannel WB, Ellison RC 1996 Alcohol and coronary heart disease: the evidence for a protective effect. Clin Chim Acta 246:59–76[CrossRef][Medline]
  18. Turner RT, Vandersteenhoven JJ, Bell NH 1987 The effects of ovariectomy and 17ß-estradiol on cortical bone histomorphometry in growing rats. J Bone Miner Res 2:115–122.[Medline]
  19. Black LJ, Sato M, Rowley ER, Magee DE, Bekele A, Williams DC, Cullinan GJ, Bendele R, Kauffman RF, Bensch WR, Frolik CA, Termine JD, Bryant HU 1994 Raloxifene (LY139481 HCl) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest 93:63–69.
  20. Murphy LJ, Murphy JW 1994 Steroid hormone induction of growth factors and oncogene expression in the uterus. In: Khan SA, Stancel GM (eds) Proto-Oncogenes and Growth Factors in Steroid Hormone Induced Growth and Differentiation. CRC Press, Boca Raton, pp 31–45
  21. Evans GL, Turner RT 1995 Tissue selective actions on estrogen analogs. Bone 17:181S–190S[CrossRef]
  22. Kauffman RF, Bensch WR, Roudebush RE, Cole HW, Bean JS, Phillips DL, Monroe A, Cullinan GJ, Glasebrook AL, Bryant HU 1997 Hypocholesterolemic activity of raloxifene (LY139481): pharmacological characterization as a selective estrogen receptor modulator. J Pharmacol Exp Ther 280:146–153[Abstract/Free Full Text]
  23. Sibonga JD, Dobnig H, Harden RM, Turner RT 1998 Effect of the high affinity estrogen receptor ligand ICI 182,780 on rat tibia. Endocrinology 139:3736–3742[Abstract/Free Full Text]
  24. Weinstein I, Wilcox HG, Heimberg M 1986 Effects of high-dose ethinyl estradiol on serum concentrations and hepatic secretion of the very-low-density lipoprotein, triacylglycerol, cholesterol, and apolipoprotein A-I in the rat. Biochim Biophys Acta 876:450–459[Medline]
  25. Turner RT, Riggs BL, Spelsberg TC 1994 Skeletal effects of estrogen. Endocr Rev 15:275–300[Abstract/Free Full Text]



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Evidence for the stimulatory effect of resveratrol on Ca2+-activated K+ current in vascular endothelial cells
Cardiovasc Res, March 1, 2000; 45(4): 1035 - 1045.
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 Hum Exp ToxicolHome page
I Slater, J Odum, and J Ashby
Resveratrol and red wine consumption
Human and Experimental Toxicology, October 1, 1999; 18(10): 625 - 626.
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