Abstract
Because dehydroepiandrosterone (DHEA) has a wide variety of weak beneficial effects in experimental animals and humans, we searched for metabolites of this steroid in the hope of finding more active compounds that might qualify for the title “steroid hormone”. Incubation of DHEA with rat liver homogenate fortified with energy-yielding substrates resulted in rapid hydroxylation at the 7α-position of the molecule and subsequent conversion to other 7-oxygenated steroids in the sequence DHEA»7α-hydroxyDHEA»7-oxoDHEA»7β-hydroxyDHFA, with branching to diols, triols, and sulfate esters. The ability of these metabolites to induce the formation of liver thermogenic enzyme activity increased from left to right in that sequence. A total of 25 different steroids were characterized, and at least six additional structures that are currently under study were produced from DHEA. 7-OxoDHEA is more effective than DHEA in enhancing memory performance in old mice and in reversing the amnesic effects of scopolamine.
Similar content being viewed by others
Abbreviations
- DHEA:
-
dehydroepiandrosterone
- DHEAS:
-
the sulfate ester of dehydroepiandrosterone
- GDPH:
-
glycerophosphate dehydrogenase
References
Horgan, J. (1997). End of Science: Facing the Limits of Knowledge in the Twilight of the Scientific Age, Addison-Wesley, Reading, MA.
Parker, L. (1989) Adrenal Androgens in Clinical Medicine, Academic Press, San Diego.
Le Goascogne, C., Robel, P., Gouezou, M., Sananes, N., Baulieu, E.E., and Watermen, M. (1987) Neurosteroids: Cytochrome P450ssc in Rat Brain, Science 237, 1212–1215.
Yen, T.T., Allan, J.A., Pearson, D.V., Acton, J.M., and Greenberg, M.M. (1977) Prevention of Obesity in Avy/a Mice by Dehydroepiandrosterone, Lipids 12, 409–413.
Cleary, M.P. (1989) Antiobesity Effect of Dehydroepiandrosterone in the Zucker Rat, in Hormones, Thermogenesis, and Obesity (Lardy, H., and Stratman, F., eds.), pp. 365–376, Elsevier, New York.
Kurzman, I.D., MacEwen, E.G., and Haffa, L.M. (1990) Reduction in Body Weight and Cholesterol in Spontaneously Obese Dogs by Dehydroepiandrosterone, Int. J. Obes., 14, 95–104.
Lee-Currie, Y.R., Wen, P., and McIntosh, M.K., (1997) Dehydroepiandrosterone-Sulfate (DHEAS) Reduces Adipocyte Hyperplasia Associated with Feeding Rats a High-Fat Diet, Int. J. Obes. 21, 1058–1064.
Kurzman, I.D., Panciera, D., Miller, J.B., and MacEwen, E.G. (1998) The Effect of Dehydroepiandrosterone Combined with a Low-Fat Diet in Spontaneously Obese Dogs: A Clinical Trial, Obes. Res. 6, 20–28.
Kritchevsky, D., Tepper, S., Klurfeld, D., and Schwartz, A.S. (1983) Influence of Dehydroepiandrosterone (DHEA) on Cholesterol Metabolism in Rats, Pharmacol. Res. Commun. 15, 797–803.
Ben-David, M., Dikstein, S., Bismuth, G., and Sulman, F.G. (1967) Antihypercholesterolemic Effect of Dehydroepiandrosterone in Rats, Proc. Soc. Exp. Biol. Med. 125, 1136–1140.
Coleman, D.L., Schwizer, R.L., and Leiter, E.H. (1984) Effect of Genetic Background on the Therapeutic Effects of Dehydroepiandrosterone (DHEA) in Diabetes-Obesity Mutants and in Aged Normal Mice, Diabetes 33, 26–32.
Loria, R., Inge, T.H., Cook, S.S., Szakol, A., and Regelson, W. (1988) Protection Against Acute Lethal Viral Infections with the Native Steroid Dehydroepiandrosterone (DHEA), Med. Virol. 26, 301–314.
Ben-Nathan, D., Lustig, S., Kobilar, D., Danenberg, H.D., Lupu, E., and Feuerstein, G. (1992) Dehydroepiandrosterone Protects Mice Inoculated with West Nile Virus and Exposed to Cold Stress, J. Med. Virol. 38, 159–166.
Schwartz, A.G. (1979) Inhibition of Spontaneous Breast Cancer Formation in Female C3H(Avy/a) Mice by Long-Term Treatment with Dehydroepiandrosterone, Cancer Res. 39, 1129–1132.
Nyce, J.W., Magee, P.N., Hard, G.C., and Schwartz, A.G. (1984) Inhibition of 1,2-Dimethylhydrazine-Induced Colon Tumorigenesis in Balb/c Mice by Dehydroepiandrosterone, Carcinogeneis 5, 57–62.
Flood, J.F., Smith, G.E., and Roberts, E. (1988) Dehydroepiandrosterone and Its Sulfate Enhance Memory Retention in Mice, Brain Res. 447, 269–278.
Flood, J.F., and Roberts, E. (1988) Dehydroepiandrosterone Sulfate Improves Memory in Aging Mice, Brain Res. 448, 178–181.
Kalimi, M., and Regelson, W. (eds.) (1990) The Biological Role of Dehydroepiandrosterone (DHEA), DeGruyter, Berlin.
Mortola, J.F., and Yen, S.S. (1990) The Effects of Oral Dehydroepiandrosterone on Endocrine-Metabolic Parameters in Postmenopausal Women, J. Clin. Endocrinol. Metab. 71, 696–704.
Morales, A.J., Nolan, J.J., Nelson, J.C., and Yen, S.S. (1994) Effects of Replacement Doses of Dehydroepiandrosterone in Men and Women of Advancing Age, J. Clin. Endocrinol. Metab. 78, 1360–1367.
Labrie, F., Diamond, P., Cusan, L., Gomez, J.-L., Belanger, A., and Candas, B. (1997) Effect of 12-Month Dehydroepiandrosterone Replacement Therapy on Bone, Vagina, and Endometrium in Postmenopausal Women, J. Clin. Endocrinol. Metab. 82, 3498–3505.
Morales, A.J., Haubrich, R.H., Hwang, J.Y., Asakura, H., and Yen, S.S. (1998) The Effect of Six Months Treatment with a 100 mg Daily Dose of Dehydroepiandrosterone (DHEA) on Circulating Sex Steroids, Body Composition and Muscle Strength in Age-Advanced Men and Women, Clin. Endocrinol. 49, 421–432.
Labrie, F. (1998) DHEA as a Physiological Replacement Therapy at Menopause, J. Endocrinol. Invest. 21, 399–401.
Barry, N.N., McGuire, J.L., and van Vollenhoven, R. (1998) Dehydroepiandrosterone in Systemic Lupus Erythematosus: Relationship Between Dosage, Serum Levels, and Clinical Response, J. Rheumatol. 27, 2352–2356.
Bloch, M., Schmidt, P.J., Danaceau, M., Adams, L.F., and Rubinow, D.R. (1999) Dehydroepiandrosterone Treatment of Midlife Dysthymia, Biol. Psychiatry 45, 1533–1541.
van Vollenhoven, R.F. (2000) Dehydroepiandrosterone in Systemic Lupus Erythematosus, Rheum. Dis. Clin. North Am. 26, 349–362.
Arlt, W., Callies, F., and Allolio, B. (2000) DHEA, Replacement in Women with Adrenal Insufficiency: Pharmacokinetics, Bioconversion, and Clinical Effects on Well-Being, Sexuality, and Cognition, Endocr. Res. 26, 505–511.
Allen, E., and Doisy, E.A. (1923) An Ovarian Hormone. Preliminary Report on Its Location, Extraction and Partial Purification, and Action in Test Animals, J. Am. Med. Assoc. 81, 819–821.
Bucher, T., and Klingenberg, M. (1958) Weg des Wasserstoffs in der lebendigen Organization, Angew. Chem. 70, 552–570.
Estabrook, R.W., and Sacktor, B. (1958) α-Glycerophosphate Oxidase of Flight Muscle Mitochondria, J. Biol. Chem. 233, 1014–1019.
Harington, C.R. (1933) The Thyroid Gland, Its Chemistry and Physiology, Oxford University Press, London.
Cori, G.T. (1921) Experimentelle untersuchungen an einem kongenitalen Myxodem, Z. Ges. Exper. Med. 25, 150–169.
Plummer, H.S., and Boothby, W.M. (1923) The Cost of Work in Exophthalmic Goiter, Am. J. Physiol. 63, 406–407.
Briard, S.P., McClintock, J.T., and Baldridge, C.W. (1935) Cost of Work in Patients with Hypermetabolism Due to Leukemia and to Exophthalmic Goiter, Arch. Int. Med. 56, 30–37.
Lee, Y.-P., Takemori, A., and Lardy, H. (1959) Enhanced Oxidation of α-Glycerophosphate by Mitochondria of Thyroid-Fed Rats, J. Biol. Chem. 234, 3051–3054.
Lee, Y.-P., and Lardy, H.A. (1965) Influence of Thyroid Hormones on l-α-Glycerophosphate Dehydrogenase and Other Dehydrogenases in Various Organs of the Rat, J. Biol. Chem. 240, 1427–1436.
Tagliaferro, A., Davis, J.R., Truchon, S., and Van Hamont, N. (1986) Effects of Dehydroepiandrosterone Acetate on Metabolism, Body Weight, and Composition of Male and Female Rats, J. Nutr. 116, 1977–1983.
Lardy, H., Su, C.-Y., Kneer, N., and Wielgus, S. (1989) Dehydroepiandrosterone Induces Enzymes That Permit Thermogenesis and Decrease Metabolic Efficiency, in Hormones, Thermogenesis, and Obesity (Lardy, H., and Stratman, F., eds.), pp. 415–426, Elsevier, New York.
Su, C.-Y., and Lardy, H.A. (1991) Induction of Hepatic Glycerophosphate Dehydrogenase in Rats by Dehydroepiandrosterone, J. Biochem. (Tokyo) 110, 207–213.
Lardy, H. (1999) Dehydroepiandrosterone and Ergosteroids Affect Energy Expenditure, in Health Promotion and Aging: The Role of Dehydroepiandrosterone (DHEA) (Watson, R.R., ed.), p. 33–42, Harwood, Amsterdam.
Lardy, H., Paetkau, V., and Walter, P. (1965) Paths of Carbon in Gluconeogenesis and Lipogenesis: The Role of Mitochondria in Supplying Precursors of Phosphoenolpyruvate, Proc. Natl. Acad. Sci. USA 53, 1410–1415.
Bobyleva, V., Kneer, N., Bellei, M., Battelli, D., and Lardy, H. (1993) Concerning the Mechanism of Increased Thermogenesis in Rats Treated with Dehydroepiandrosterone, J. Bioenerg. Biomembr. 25, 313–321.
Lardy, H., Partridge, B., Kneer, N., and Wei, Y. (1995) Ergosteroids: Induction of Thermogenic Enzymes in Liver of Rats Treated with Steroids Derived from Dehydroepiandrosterone, Proc. Natl. Acad. Sci. USA 92, 6617–6619.
Lardy, H., Kneer, N., Wei, Y., Partridge, B., and Marwah, P. (1998) Ergosteroids II: Biologically Active Metabolites and Synthetic Derivatives of Dehydroepiandrosterone, Steroids 63, 158–165.
Reich, I.L., Lardy, H., Wei, Y., Marwah, P., Kneer, N., Powell, D.R., and Reich, H.J. (1998) Ergosteroids III: Syntheses and Biological Activity in Secosteroids Related to Dehydroepiandrosterone, Steroids 63, 542–553.
Marwah, P., Marwah, A., Kneer, N., and Lardy, H. (2001) Ergosteroids IV: Synthesis and Biological Activity of Steroid Glucuronides, Ethers, and Alkylcarbonates, Steroids 66, 581–595.
Reich, I.L., Reich, H.J., Kneer, N., and Lardy, H. (2002) Erosteroids V: Preparation and Biological Activity of Various D-Ring Derivatives in the 7-Oxo-dehydroepiandrosterone Series, Steroids 67, 221–233.
Marwah, A., Marwah, P., and Lardy, H. (2002) Ergosteroids VI: Metabolism of Dehydroepiandrosterone in vitro: A Liquid Chromatographic-Mass Spectrometric Study, J. Chromatogr. B 767, 285–299.
Marwah, A., Marwah, P., and Lardy, H. (2001) High-Performance Liquid Chromatographic Analysis of Dehydroepiandrosterone, J. Chromatogr. A 935, 279–296.
Shi, J., Schulze, S., and Lardy, H. (2000) The Effect of 7-Oxo-DHEA Acetate on Memory in Young and Old C57BL/6 Mice, Steroids 65, 124–129.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Lardy, H., Marwah, A. & Marwah, P. Transformations of DHEA and its metabolites by rat liver. Lipids 37, 1187–1191 (2002). https://doi.org/10.1007/s11745-002-1019-7
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s11745-002-1019-7