The Effects of Estrogenic Carboxylic Acids on Physiology and Metabolism

Introduction

Estrogens have physiological effects on males as well as females. In addition to their activity in reproductive tissues, they have a number of other biological effects in humans and animals. These include reducing susceptablility to osteoporosis; ameliorating menopausal and postmenopausal symptoms; promotion of cardiovascular health; promotion of rapid weight gain; and slowing some of the degenerative effects of Alzeheimer's disease.

Non-steroidal estrogens and antiestrogens, including pharmaceuticals, environmental compounds, and phytochemicals, are currently receiving significant attention. These compounds have potential applications in treating menopause and post-menopause-related problems; use as anti-carcinogens; alleviating osteoporosis; for contraceptive use; in estrogen-replacement therapy; treatment of prostatic disease; improvement of lipid profiles; among other potential applications.

Doisynolic acids are non-steroidal estrogenic compounds originally created and named for Edward Doisy and colleagues. They were originally synthesized using an alkaline fusion of estrone and equilenin. Our research is examining the effects of these compounds on mammalian physiology, metabolism, and health.

Objectives:

Specific objectives of our studies are:

1. To synthesize and manipulate Z-bis-dehydrodoisynolic acid (BDDA) compounds and seperate enatiomers from the organic synthesis.

2. To determine the interaction of BDDAs on forms of the estrogen receptor in terms of receptor binding and transcriptional activity.

3. To investigate the effects of BDDAs on weight gain, food consumption, and body compositition of male and female rats, especially as related to cardiovascular health.

4. To determine the effects of BDDAs on reproductive parameters in rats and pigs.

5. To investigate the biochemistry and physiological effects of other estrogenic carboxylic acids.

Patents:

Meyers, C.Y. 1995. Doisynolic Acid Type Compounds as Weight and Appetitie Suppressing and Control Agents. U.S. Patent No. 5,420,161.

Meyers, C.Y., W.J. Banz, S.R. Adler, T.A. Winters, Y-Q. Hou, W.B. Dandliker. 1998. Therapeutic Applications of Estrogenic Carboxylic Acids. U.S. Provisional Patent Disclosure filed June 23, 1998; International Patent Application June 22, 1999; U.S. Patent Application June 23, 1999. Patent Serial # 60/090,344.

Hou, Y. 1999. One-Pot Asymmetric Synthesis of Estrogenic (+)- and (-) Vallestril (Allenoic Acid), Patent Pending.

Publications:

Meyers, C.Y., V.M. Kolb. 1978. Facile and Selective Chlorination-Cleavage of Some Cyclanones and Cyclanols with the CCl4-KOH-t-BuOH Reagent. In Situ Conversion of Estrones and Estradiols into Dichlorodoisynolic Acids. J. Org. Chem. 43:1985-90.

Dandliker, W.B., R.J. Brawn, M-L. Hsu, P.N. Braun, J. Levin, C.Y. Meyers, V.M. Kolb. 1978. Investigation of hormone-receptor interactions by means of fluorescence labeling. Cancer Res. 38:4212-4224.

Nenci, I., W.B. Dandliker, C.Y. Meyers, E. Marchetti, A. Marzola, G. Fabris. 1980. Estrogen Receptor Cytochemistry by Fluorescent Estrogen. J. Histochem. and Cytochem. 28:1081-88.

Meyers, C.Y., V.M.Kolb; W.B. Dandliker. 1982. Doisynolic Acids: Potent Estrogens with Very Low Affinity for Estrogen Receptors. Res. Commun. Chem. Pathol. Pharmacol. 35:165-168.

Meyers, C.Y. 1984. The role of hormone receptors in estrogen activity is questionable. Trends in Biochem. Sci. 9:473.

Meyers, C.Y., V.M. Kolb, G.H. Gass, B.R. Rao, C.F. Roos, W.B. Dandliker. 1988. Doisynolic Acids: Uterotropically potent estrogens which compete poorly with estradiol for cytosolic estradiol receptors. J. Steroid Biochem. 31:393-404.

Soto, A.M., C.Y. Meyers, C. Sonnenschein. 1988. How many rings can be cleaved from a steroidal estrogen while preserving its estrogenic activity? 70th Annual Meeting of the Endocrine Society. Abstract #1301.

Meyers, C.Y. and S. Adler. 1997. Estrogenic Activities of Environmental Endocrine Disruptors. 79th Annual Meeting of the Endocrine Society, Minneapolis, MN, June 11-14. Abstract P1-544.

Meyers, C.Y., H. Lufti, and S. Adler. 1997. Transcriptional regulation of estrogen-responsive genes by non-steroidal estrogens: Doisynolic and allenolic acids. J. Steroid Biochem. Mol. Biol. 62:477-489.

Banz, W.J., T.A. Winters, Y-Q. Hou, C.Y. Meyers, M.A. Mallon, and S. Adler. 1998. Activities of non-classical estrogens: Effects of (-), (+), and (+/-) z-bis-dehydrodoisynolic acids in vitro and on body weight in male and female rats. 80th Annual Meeting of the Endocrine Society, New Orleans, LA., June 24. Abstract #1

Banz, W.J., T.A. Winters, Y-Q. Hou, S. Adler, and C.Y. Meyers. 1998. Comparative effects of the selective estrogen receptor modulators (-)-, (+)- and (+/-)-Z-bisdehydodoisynolic acids on metabolic and reproductive parameters in male and female rats. Presentation at the 7th Annual University of Wisconsin Endocrinology-Reproductive Physiology Program Research Symposium, Madison, WI. September 4., Poster Presentation Abstract #1

Suttner, A.M., W.J. Banz, Y-Q. Hou, C.Y. Meyers, S. Adler, and T.A. Winters. 1998. The effects of Z-bis dehydrodoisynolic acids on in situ apopotosis in primary porcine granulosa cells. Presentation at the 7th Annual University of Wisconsin Endocrinology- Reproductive Physiology Program Research Symposium, Madison, WI. September 4., Oral Presentation Abstract #8

Wilson, T., H. March, W.J. Banz, Y. Hou, S. Adler, C.Y. Meyers, T.A. Winters, and M.A. Maher. 1998. Antioxidant effects of phyto- and synthetic estrogens on Cu++-induced oxidation of human low density lipoproteins (LDL). Presentation at the 7th Annual University of Wisconsin Endocrinology-Reproductive Physiology Program Research Symposium, Madison, WI. September 4., Poster Presentation Abstract #25.

Banz, W.J., T.A. Winters, Y-Q. Hou, S.R. Adler, and C.Y. Meyers. 1998. Comparative effects of the selective estrogen receptor modulators (-)-, (+)- and (±)-Z-bisdehydrodoisynolic acids on metabolic and reproductive parameters in male and female rats. Horm. Metab. Res.30:730-736.

Robinson, P.D., Y-Q. Hou, C.Y. Meyers, W.J. Banz, and T.A. Winters. 1999. L-menthyl ester of highly estrogenic (-)-Z-bisdehydrodoisynolic acid 3-methyl ether. Acta Crystallogr. C55, April, CIF-Access paper IUC9900020.

Wilson, T., H. March, W.J. Banz, Y. Hou, S. Adler, C.Y. Meyers, T.A. Winters, and M.A. Maher. 1999 Antioxidant effects of phyto- and synthetic estrogens on Cu++-induced oxidation of human low density lipoproteins (LDL). Annual (FASEB) Experimental Biology Meeting, Washington, D.C. April 20. Abstract 676.13, pg. A905.

Meyers, C.Y., Y. Hou, P.D. Robinson, S. Adler, W.J. Banz, and T.A. Winters. 2000. Absolute structure determination of highly estrogenic bisdehydrodoisynolic acid. J. Pharm. Sci. 89(4):513-518.

Winters, T., W. Banz, J. Cameron, M. McDearmon, L. Debeljuk, J. Huggenvik, M. Collard, C. Meyers, Y. Hou, S. Adler, and W. Dandliker. 2000. Differential effects of estrogenic carboxylic acids on the testis and prostate. Annual (FASEB) Experimental Biology Meeting, San Diego, CA, April 18. Abstract 469.3. FASEB J. 14(4):A652

Ellis, S.A., D. Perseli, M.J. Roeder, Y. Hou, S. Adler, C.Y. Meyers, W.J. Banz, and T.A. Winters. 2001 Effects of bisdehydrodoisynolic acids on the reproductive histology of female rats. Abstract #566. Biol. Reprod. 64:(Suppl. 1):328.

Henry, N., Y. Hou, M.J. Roeder, J. Feldmeier, J. Patton, W.J. Banz, S. Adler, C.Y. Meyers, and T.A.Winters. 2001. Effects of (+)-Z-bisdehydrodoisynolic acid on the rat prostate. Abstract #308. Biol. Reprod. 64:(Suppl. 1):227.

Miller, K.J., S.A. Ellis, M.J. Roeder, Y. Hou, S. Adler, C.Y. Meyers, W.J. Banz, and T.A. Winters. 2002. Effects of Bisdehydrodoisynolic Acids on Rat Uterine Connective Tissue and Smooth Muscle Composition using a Novel Approach. Proceedings of the 8th Annual Southern Illinois University Molecular and Cellular Biology Symposium, Pere Marquette Lodge, Grafton, IL, Mar. 2, Poster Abstract.

Henry, N.R., C.Y. Meyers, Y.Hou, S. Adler, M.J. Roeder, K.J. Miller, D. Murdoch, M.S. Bonkowski, and T.A. Winters. 2002. (+)-Z-Bisdehydrodoisynolic Acid: Paradoxical Effects in the Male Rat Reproductive System. Proceedings of the 8th Annual Southern Illinois University Molecular and Cellular Biology Symposium, Pere Marquette Lodge, Grafton, IL, Mar. 2, Poster Abstract.

Meyers, C.Y., Y-Q. Hou, T.A. Winters, W.J. Banz, M.A. Mallon, and S. Adler. 2002. Activities of a non-classical estrogen, z-bis-dehydrodoisynolic acid, with ER and ER . J. Steroid Biochem.. Mol. Biol. 82(1):33-44.

Wilson, T., H. March, W.J. Banz, Y. Hou, S. Adler, C.Y. Meyers, T.A. Winters, and M.A. Maher. 2002. Antioxidant effects of phyto- and synthetic estrogens on cupric ion-induced oxidation of human low density lipoproteins in vitro. Life Sci. 70:2287-2298.

Related Research Project:

Soy Phytoestrogens: Effects on Physiology and Health

Interactions between Vitamins and Dietary Phytoestrogen on Prostate Disease

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~~~~~Revised 1/24/03~~~~~ TAW