Background and Aim: The phytoestrogen resveratrol is found in grapes, mulberries and peanuts, all of which are consumed regularly by humans. Resveratrol is also used in chemotherapy against cancer and aging and as a cardioprotectant. The aim of the present study was to characterize the effects of resveratrol on rat adrenal steroidogenesis and to study the underlying mechanism. Methods: Adrenocortical cells were isolated from the adrenal glands of normal male rats (in vitro) and from male rats administered resveratrol in their diet for 12 weeks (ex vivo). Cells from resveratrol-treated and non-treated rats were tested ex vivo for responsiveness to ACTH and cells from normal rats were tested in vitro for responsiveness to ACTH in the presence and absence of resveratrol. Corticosterone and progesterone production were measured by RIA and expression of steroidogenic enzymes analyzed by PAGE/Western blotting. Results: Corticosterone production was inhibited 47% by 50 µM resveratrol in vitro and 20% ex vivo, while progesterone production was elevated to 400% of the control value in in vitro experiments. Resveratrol treatment decreased adrenal cytochrome P450 c21-hydroxylase expression in vivo and cell culture conditions. No changes in cell viability or morphology were caused by exposure to resveratrol in both ex vivo and in vitro experiments. Conclusion: Resveratrol suppresses corticosterone production by primary rat adrenocortical cell cultures in vitro and ex vivo by inhibiting cytochrome P450 c21-hydroxylase.

Keywords:
Resveratrol, Cytochrome P450 c21-hydroxylase, Adrenocortical steroidogenesis, Corticosterone, Progesterone
1.
Fisher JS: Environmental anti-androgens and male reproductive health: Focus on phthalates and testicular dysgenesis syndrome. Reproduction 2004;127:305–315.
2.
Crowell JA, Korytko PJ, Morrissey RL, Booth TD, Levine BS: Resveratrol-associated renal toxicity. Toxicol Sci 2004;82:614–619.
3.
Mesiano S, Katz SL, Lee JY, Jaffe RB: Phytoestrogens alter adrenocortical function: Genistein and daidzein suppress glucocorticoid and stimulate androgen production by cultured adrenal cortical cells. J Clin Endocrinol Metab 1999;84:2443–2448.
4.
Li W, Seifert M, Xu Y, Hock B: Comparative study of estrogenic potencies of estradiol, tamoxifen, bisphenol-A and resveratrol with two in vitro bioassays. Environ Int 2004;30:329–335.
5.
Siemann EH, Creasy LL: Concentration of the phytoalexin resveratrol in wine. Am J Enol Vitic 1992;43:49–52.
6.
Gehm BD, McAndrews JM, Chien PY, Jameson JR: Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci USA 1997;94:14138–14143.
7.
Di S, Zhang Z, Wang Y, Shi W: Analysis for four isomers of resveratrol in red wine by high performance liquid chromatography. Se Pu 2004;22:424–427.
8.
Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM: Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science1997;275:21820.
9.
Alarcón C, Villegas I: Review: Resveratrol as an anti-inflammatory and anti-aging agent: Mechanisms and clinical implications. Mol Nutr Food Res 2005;49:405–430.
10.
Frankel EN, Waterhouse AL, Kinsella JE: Inhibition of human LDL oxidation by resveratrol. Lancet 1993;341:1103–1104.
11.
Bertelli AA, Giovannini L, Giannessi D, Migliori M, Bernini W, Fregoni M, Bertelli A: Antiplatelet activity of synthetic and natural resveratrol in red wine. Int J Tiss React 1995;17:1–3.
12.
Pace-AsciakCR, Hahn S, DiamandisEP, SoleasG, GoldbergDM: 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 1995;235:207–219.
13.
Goldberg DM, Hahn SE, Parkes JG: Beyond alcohol: beverage consumption and cardiovascular mortality. Clin Chim Acta 1995;237:155–187.
14.
Marier J-F, Vachon P, Gritsas A, Zhang J, Morean J-P, Ducharme MP: Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model. J Pharmacol Exp Ther 2002;302:369–373.
15.
Preziosi P: Natural and anthropogenic environmental oestrogens: the scientific basis for risk assessment. Endocrine disrupters as environmental signalers: an introduction. Pure Appl Chem 1998;70:1617–1631.
16.
Ohno S, Nakajima Y, Inoue K, Nakazawa H, Nakajin S: Genistein administration decreases serum corticosterone and testosterone levels in rats. Life Sci 2003;74:733–742.
17.
Kristan K, Krajnc K, Konc J, Gobec S, Stojan J, Rizner TL: Phytoestrogens as inhibitors of fungal 17beta-hydroxysteroid dehydrogenase. Steroids 2005;70:694–703.
18.
Frémont L: Minireview: Biological effects of resveratrol. Life Sci 2000;66:663–673.
19.
Kowalski J, Samojedny A, Paul M, Pietsz G, Wilczok T: Effect of apigenin, kaempferol and resveratrol on the expression of interleukin-1beta and tumor necrosis factor-alpha genes in J774.2 macrophages. Pharmacol Rep 2005;57:390–394.
20.
Gell JS, Oh J, Rainey WE, Carr BR: Effect of estradiol on DHEAS production in the human adrenocortical cell line, H295R. J Soc Gynecol Invest 1998;5:144–148.
21.
Mesiano S, Jaffe RB: Interaction of insulin-like growth factor-II and estradiol directs steroidogenesis in the human fetal adrenal toward dehydroepiandrosterone sulfate production. J Clin Endocrinol Metab 1993;77:754–758.
22.
Osborne CK, Zhao H, Fuqua SAW: Selective estrogen receptor modulators: structure, function, and clinical use. J Clin Oncol 2000;18:3172–3186.
23.
Akingbemi BT, Ge R, Rosenfeld CS, Newton LG, Hardy DO, Catterall JF, Lubahn DB, Korach KS, Hardy MP: Estrogen receptor-alpha gene deficiency enhances androgen biosynthesis in the mouse Leydig cell. Endocrinology 2003;144:84–93.
24.
Culpitt SV, Rogers DF, Fenwick PS, Shah P, De Matos C, Russell RE, Barnes PJ, Donnelly LE: Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in COPD. Thorax 2003;58:942–946.
25.
Tominaga T, Fukata J, Naito Y, Usui T, Murakami N, Fukushima M, Nakai Y, Hirai Y, Imura H: Prostaglandin-dependent in vitro stimulation of adrenocortical steroidogenesis by interleukins. Endocrinology 1991;128:526–531.
26.
Path G, Scherbaum WA, Bornstein SR: The role of interleukin-6 in the human adrenal gland. Eur J Clin Invest 2000;30(suppl 3):91–95.
© 2005 S. Karger AG, Basel
2005
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.