The influence of 4-hydroxy-4-androstene-3,17-dione on androgen metabolism and action in cultured human foreskin fibroblasts |
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| Authors: | Y H Hsiang G D Berkovitz T R Brown C J Migeon A M Brodie |
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| Institution: | 1. The Division of Pediatric Endocrinology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A.;1. Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.;1. Department of Pharmacology, Vanderbilt University, 37232, Nashville, TN, USA;2. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, 37232, Nashville, TN, USA;3. Center for Cognitive Medicine, Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, 37212, Nashville, TN, USA;4. Geriatric Research, Education, and Clinical Center (GRECC), Tennessee VA Health Systems, 37212, Nashville, TN, USA;1. Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, United States;2. Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, United States;3. Duke Institute for Brain Sciences (DIBS), Durham, NC 27710, United States;1. Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan;2. Department of Chemistry & Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, United Kingdom;3. Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany;4. Leibniz Institut für Katalyse an der Universität Rostock e.V. (LIKAT), Albert-Einstein-Str. 29a, 18059 Rostock, Germany;1. Faculty of Pharmacy, Shaanxi University of Science & Technology, Xi’an, 710021, PR China;2. Medical College, Guizhou University, Guiyang, 550025, PR China;3. Zhuhai Jinan Selenium Source Nanotechnology Co., Ltd., Hengqin, Zhuhai, Guangdong, 519030, PR China;4. Shaanxi Panlong Pharmaceutical Group Co., Ltd., Xi’an, 710025, PR China;5. Laboratory for Medicinal Chemistry (FFW), Ghent University, Ottergemsesteenweg 460, B9000, Gent, Belgium;1. Protein Crystallography Section, Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India;2. Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India;1. Endocrinology Unit, Medical Department, Azienda Usl, Maggiore-Bellaria Hospital, Bologna, Italy;2. Andrology, Women''s Endocrinology and Gender Incongruence Unit, “Mario Serio” Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy;3. Endocrinology Unit, “Mario Serio” Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy |
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| Abstract: | 4-hydroxy-4-androstene-3,17-dione (4-OHA) has been shown to be a potent inhibitor of aromatase activity. It is effective in the control of estrogen-dependent processes in female subjects and may potentially be useful in the treatment of estrogen-dependent processes in men. Human foreskin fibroblasts grown in cell culture provide a model to investigate the effects of 4-OHA on extraglandular aromatase activity as well as the ability of the compound to influence androgen receptor binding and the 5 alpha-reduction of testosterone (T). Initial experiments were carried out to determine the potency of 4-OHA in genital skin fibroblasts by incubating cells with 4-OHA over a range of concentrations. When aromatase activity was determined at a substrate concentration close to the apparent Km of the enzyme, a 44% inhibition of enzyme activity occurred at a mean concentration of 5 nM 4-OHA. Enzyme kinetic studies analyzed by Eadie-Hofstee plots demonstrated competitive inhibition by 4-OHA with a mean apparent Ki of 2.7 nM. When 5 alpha-reductase activity was determined in the presence of 200 nM 3H]T, in the absence or presence of 4-OHA, a 50% inhibition of enzyme activity occurred at an inhibitor concentration of 3 microM. In androgen receptor binding studies, 4-OHA possessed 1% of the affinity of dihydrotestosterone (DHT) for 3H]DHT binding sites. In summary: 4-OHA is a potent and specific inhibitor of aromatase activity in human genital skin fibroblasts, the affinity of the enzyme for 4-OHA being greater than its affinity for the substrate, androstenedione. The influence of 4-OHA on 5 alpha-reductase activity and androgen receptor binding is minimal. |
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