5Α-Androstane-3Α, 17Β-Diolglucuronide (3 Αdiol
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Effects of Aminoglutethimide on A5-Androstenediol Metabolism in Postmenopausal Women with Breast Cancer1
[CANCER RESEARCH 42, 4797-4800, November 1982] 0008-5472/82/0042-0000802.00 Effects of Aminoglutethimide on A5-Androstenediol Metabolism in Postmenopausal Women with Breast Cancer1 Charles E. Bird,2 Valerie Masters, Ernest E. Sterns, and Albert F. Clark Departments of Medicine [C. E. B., V. M.], Surgery [E. E. S.J, and Biochemistry [A. F. C.], Queen s University and Kingston General Hospital, Kingston, Ontario, Canada K7L 2V7 ABSTRACT women. More recently, we (8) and others (18) reported that the production of A5-androstene-3/8,17/8-diol in normal post- A5-Androstene-3/8,1 7/S-diol has potential estrogenic activity menopausal women is approximately 500 to 700 fig/24 hr. because it is known to bind to receptors and translocate to the AG, in combination with hydrocortisone, has been utilized to nucleus of certain estrogen target tissues. Its role in the biology inhibit estrogen production in patients with breast cancer (21 ). of breast cancer is unclear. Aminoglutethimide plus hydrocor This form of therapy has been termed "medical adrenalec tisone ("medical adrenalectomy") has been used to treat post- tomy," and studies suggest that it is as effective as surgical menopausal women with metastatic breast cancer. adrenalectomy. The hydrocortisone shuts off the basal adre- We studied A5-androstene-3/3,17/?-diol metabolism in post- nocortical production of estrogen precursors; AG not only menopausal women with breast cancer before and during slows down steroid biosynthesis at an early step but also aminoglutethimide-plus-hydrocortisone therapy, utilizing the specifically inhibits the aromatization of A4-androstenedione to constant infusion technique. -
Perinatal Bisphenol a Exposure Increases Atherosclerosis in Adult Male PXR-Humanized Mice
RESEARCH ARTICLE Perinatal Bisphenol A Exposure Increases Atherosclerosis in Adult Male PXR-Humanized Mice Yipeng Sui,1 Se-Hyung Park,1 Fang Wang,1 and Changcheng Zhou1 1Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536 Bisphenol A (BPA) is a base chemical used extensively in numerous consumer products, and human exposure to BPA is ubiquitous. Higher BPA exposure has been associated with an increased risk of atherosclerosis and cardiovascular disease (CVD) in multiple human population-based studies. However, the underlying mechanisms responsible for the associations remain elusive. We previously reported that BPA activates the xenobiotic receptor pregnane X receptor (PXR), which has proa- therogenic effects in animal models. Because BPA is a potent agonist for human PXR but does not 2 2 affect rodent PXR activity, a suitable PXR-humanized apolipoprotein E–deficient (huPXR•ApoE / ) mouse model was developed to study BPA’s atherogenic effects. Chronic BPA exposure increased atherosclerosis in the huPXR•ApoE2/2 mice. We report that BPA exposure can also activate human PXR signaling in the heart tubes of huPXR•ApoE2/2 embryos, and perinatal BPA exposure exac- erbated atherosclerosis in adult male huPXR•ApoE2/2 offspring. However, atherosclerosis devel- opment in female offspring was not affected by perinatal BPA exposure. Perinatal BPA exposure did not affect plasma lipid levels but increased aortic and atherosclerotic lesional fatty acid transporter 2 2 CD36 expression in male huPXR•ApoE / offspring. Mechanistically, PXR epigenetically regulated CD36 expression by increasing H3K4me3 levels and decreasing H3K27me3 levels in the CD36 promoter in response to perinatal BPA exposure. The findings from the present study contribute to our understanding of the association between BPA exposure and increased atherosclerosis or CVD risk in humans, and activation of human PXR should be considered for future BPA risk assessment. -
Androstane-3\G=A\,17\G=B\-Dioland 5\G=A\-Androstane\X=Req-\ 3\G=B\,17\G=B\-Diolby Rat Testicular Cells in Vitro R
Age-related changes in conversion of 5\g=a\-androstan-17\g=b\-ol\x=req-\ 3-one to 5\g=a\-androstane-3\g=a\,17\g=b\-dioland 5\g=a\-androstane\x=req-\ 3\g=b\,17\g=b\-diolby rat testicular cells in vitro R. C. Cochran, A. W. Schuetz and L. L. Ewing Division ofReproductive Biology, Department ofPopulation Dynamics, The Johns Hopkins University, School ofHygiene and Public Health, Baltimore, Maryland 21205, U.SA. Summary. Conversion of labelled 5\g=a\-androstan-17\g=b\-ol-3-one(DHT) by isolated testicular cells from rats of different ages was examined under saturating substrate conditions in vitro (5\p=n-\10\g=m\gDHT/ml in a 24 h incubation). Two detectable metabolites of DHT were produced by testicular cells in vitro, 5\g=a\-androstane\x=req-\ 3\g=a\-17\g=b\-diol(3\g=a\-diol)and 5\g=a\-androstane-3\g=b\,17\g=b\-diol(3\g=b\-diol).Production of these diols during a 24 h period was linear, and the amounts formed were directly related to the cell number. The amount of 3\g=a\-and 3\g=b\-diolsformed by testicular cells of rats of different ages increased from Day 10 to Day 25, then declined. Testicular cells from rats 10 to 20 days of age converted DHT mainly to 3\g=a\-diol,but thereafter 3\g=b\\x=req-\ diol was the predominant testicular metabolite of DHT. Introduction Testosterone is the major metabolite of progesterone in testicular tissue sUce preparations taken from rats aged 0-17 days (Ficher & Steinberger, 1968). -
New Mechanisms and Chemicals
Copyedited by: OUP MINI REVIEW Environmental Obesogens and Their Impact on Susceptibility to Obesity: New Mechanisms and Chemicals Riann Jenay Egusquiza1,2 and Bruce Blumberg1,2,3 Downloaded from https://academic.oup.com/endo/article-abstract/161/3/bqaa024/5739626 by guest on 01 May 2020 1Department of Developmental and Cell Biology, University of California Irvine, Irvine, California 92697- 2300; 2Department of Pharmaceutical Sciences, University of California Irvine, Irvine, California 92697; and 3Department of Biomedical Engineering, University of California Irvine, Irvine, California 92697 ORCiD numbers: 0000-0002-6731-1087 (R. J. Egusquiza); 0000-0002-8016-8414 (B. Blumberg). The incidence of obesity has reached an all-time high, and this increase is observed worldwide. There is a growing need to understand all the factors that contribute to obesity to effectively treat and prevent it and associated comorbidities. The obesogen hypothesis proposes that there are chemicals in our environment termed obesogens that can affect individual susceptibility to obesity and thus help explain the recent large increases in obesity. This review discusses current advances in our understanding of how obesogens act to affect health and obesity susceptibility. Newly discovered obesogens and potential obesogens are discussed, together with future directions for research that may help to reduce the impact of these pervasive chemicals. (Endocrinology 161: 1–14, 2020) Key Words: obesity, obesogen, endocrine disrupting chemicals, EDCs, transgenerational, adipogenesis besity is a pandemic that has reached worldwide diseases, and cancers, and have contributed to approxi- O proportions, affecting essentially every country mately 4 million deaths worldwide between 1980 and (1). The most dramatic increase in obesity incidence has 2015 (3). -
Identification and Validation of Novel Hpxr Activators Amongst
DMD Fast Forward. Published on November 10, 2010 as DOI: 10.1124/dmd.110.035808 DMD FastThis Forward. article has not Published been copyedited on andNovember formatted. The 10, final 2010 version as maydoi:10.1124/dmd.110.035808 differ from this version. DMD #35808 Identification and Validation of Novel hPXR Activators Amongst Prescribed Drugs via Ligand-Based Virtual Screening Yongmei Pan, Linhao Li, Gregory Kim, Sean Ekins, Hongbing Wang and Peter W. Swaan Downloaded from Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201, USA; Collaborations in Chemistry, Jenkintown, PA 19046, USA (SE); Department of Pharmacology, University of Medicine & Dentistry dmd.aspetjournals.org of New Jersey (UMDNJ)-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA (SE). at ASPET Journals on September 24, 2021 1 Copyright 2010 by the American Society for Pharmacology and Experimental Therapeutics. DMD Fast Forward. Published on November 10, 2010 as DOI: 10.1124/dmd.110.035808 This article has not been copyedited and formatted. The final version may differ from this version. DMD #35808 a) Running Title: Identification of Novel hPXR Activators b) Corresponding Author: Peter W. Swaan, Ph.D., Department of Pharmaceutical Sciences, University of Maryland, 20 Penn Street, HSF2-621, Baltimore, MD 21201 USA Tel: (410) 706-0103 Fax: (410) 706-5017 Email: [email protected] Downloaded from c) Number of: Text pages: 35 dmd.aspetjournals.org Tables: 3 Figures: 6 References: 45 at ASPET Journals on September 24, 2021 Words in Abstract: 196 Words in Introduction: 546 Words in Discussion: 1,521 d) Abbreviations: hPXR, Human pregnane X receptor; LBD, ligand binding domain; XV ROC AUC, Leave-one-out cross-validation based ‘receiver operator curve’ area under the curve. -
CYP7B1-Mediated Metabolism of Dehydroepiandrosterone and 5A
CYP7B1-mediated metabolism of dehydroepiandrosterone and 5a-androstane-3b,17b-diol – potential role(s) for estrogen signaling Hanna Pettersson1, Lisa Holmberg1, Magnus Axelson2 and Maria Norlin1 1 Department of Pharmaceutical Biosciences, Division of Biochemistry, University of Uppsala, Sweden 2 Department of Clinical Chemistry, Karolinska Hospital, Stockholm, Sweden Keywords CYP7B1, a cytochrome P450 enzyme, metabolizes several steroids involved cytochrome P450; estrogen receptor; in hormonal signaling including 5a-androstane-3b,17b-diol (3b-Adiol), an hydroxylase; sex hormone; steroid estrogen receptor agonist, and dehydroepiandrosterone, a precursor for sex metabolism hormones. Previous studies have suggested that CYP7B1-dependent metab- Correspondence olism involving dehydroepiandrosterone or 3b-Adiol may play an impor- M. Norlin, Department of Pharmaceutical tant role for estrogen receptor b-mediated signaling. However, conflicting Biosciences, Division of Biochemistry, data are reported regarding the influence of different CYP7B1-related University of Uppsala, Box 578, steroids on estrogen receptor b activation. In the present study, we investi- S-751 23 Uppsala, Sweden gated CYP7B1-mediated conversions of dehydroepiandrosterone and Fax: +46 18 558 778 3b-Adiol in porcine microsomes and human kidney cells. As part of these Tel: +46 18 471 4331 studies, we compared the effects of 3b-Adiol (a CYP7B1 substrate) and E-mail: [email protected] 7a-hydroxy-dehydroepiandrosterone (a CYP7B1 product) on estrogen (Received 19 December 2007, revised 13 receptor b activation. The data obtained indicated that 3b-Adiol is a more February 2008, accepted 14 February 2008) efficient activator, thus lending support to the notion that CYP7B1 cataly- sis may decrease estrogen receptor b activation. Our data on metabolism doi:10.1111/j.1742-4658.2008.06336.x indicate that the efficiencies of CYP7B1-mediated hydroxylations of dehy- droepiandrosterone and 3b-Adiol are very similar. -
Binding Characteristics of a Major Protein in Rat Ventral Prostate Cytosol That Interacts with Estramustine, a Nitrogen Mustard Derivative of 17ß-Estradiol
[CANCER RESEARCH 39, 5155-5164, December 1979] 0008-5472/79/0039-OOOOS02.00 Binding Characteristics of a Major Protein in Rat Ventral Prostate Cytosol That Interacts with Estramustine, a Nitrogen Mustard Derivative of 17ß-Estradiol BjörnForsgren, Jan-Àke Gustafsson, Ake Pousette, and Bertil Hogberg AB Leo Research Laboratories. Pack. S-251 00 Helsingborg, Sweden [B.F.. B.H.], and Departments of Chemistry and Medical Nutrition. ¡J-ÄG.. A P.¡and Pharmacology [BH.], Karolinska Institute!. S-104 01 Stockholm 60. Sweden ABSTRACT causes atrophy of the testes and accessory sex organs; re duces the uptake of zinc by the prostate; depresses the 5a- The tissue distribution of [3H]estramustine, the dephospho- reductase, arginase, and acid phosphatase activities in the rylated metabolite of estramustine phosphate (Estracyt), in the male rat was compared to that of [3H]estradiol 30 min and 2 hr prostate; and affects lipid and carbohydrate metabolism (10, 11, 20, 29, 31 -33, 42). Although the observed effects in many following i.p. administration. In contrast to estradiol, estramus respects are similar to estrogenic effects, several experimental tine was found to be efficiently concentrated in the ventral and clinical results indicate that estramustine phosphate affects prostate gland by a soluble protein. The binding characteristics normal and neoplastic prostate tissue in a way that cannot be of this protein were studied in vitro using cytosol preparations attributed solely to its antigonadotropic or weak estrogenic of the gland. With a dextran-coated charcoal technique, the properties (15, 16, 30, 38). protein was found to bind estramustine with a broad pH opti Plym Forshell and Nilsson (35), using labeled compounds (1 mum between pH 7 and pH 8.5, with an apparent Kd of 10 to to 10 mg/kg body weight), found considerably higher levels of 30 nw, and with a binding capacity of about 5 nmol/mg cytosol radioactivity in the rat ventral prostate following i.v. -
Documentation, Codebook, and Frequencies
Documentation, Codebook, and Frequencies Surplus Sera Laboratory Component: Racial/Ethnic Variation In Sex Steroid Hormone Concentrations Across Age In US Men Survey Years: 1988 to 1991 SAS Export File: SSHORMON.XPT First Published: October 2006 Last revised: N/A NHANES III Data Documentation Laboratory Assessment: Racial/Ethnic Variation in Sex Steroid Hormone Concentrations Across Age In US Men (NHANES III Surplus Sera) Years of Coverage: 1988-1991 First Published: October 2006 Last Revised: N/A Introduction It has been proposed that racial/ethnic variation in prostate cancer incidence may be, in part, due to racial/ethnic variation in sex steroid hormone levels. However, it remains unclear whether in the US population circulating concentrations of sex steroid hormones vary by race/ethnicity. To address this, concentrations of testosterone, sex hormone binding globulin, androstanediol glucuronide (a metabolite of dihydrotestosterone) and estradiol were measured in stored serum specimens from men examined in the morning sample of the first phase of NHANES III (1988-1991). This data file contains results of the testing of 1637 males age 12 or more years who participated in the morning examination of phase 1 of NHANES III and for whom serum was still available in the repository. Data Documentation for each of these four components is given in sections below. I. Testosterone Component Summary Description The androgen testosterone (17β -hydroxyandrostenone) has a molecular weight of 288 daltons. In men, testosterone is synthesized almost exclusively by the Leydig cells of the testes. The secretion of testosterone is regulated by luteinizing hormone (LH), and is subject to negative feedback via the pituitary and hypothalamus. -
Serum Levels of 3A-Androstanediol Glucuronide in Hirsute and Non Hirsute Women
European Journal of Endocrinology (1998) 138 421–424 ISSN 0804-4643 Serum levels of 3a-androstanediol glucuronide in hirsute and non hirsute women L Falsetti, B Rosina and D De Fusco Department of Gynaecological Endocrinology, University of Brescia, Italy (Correspondence should be addressed to L Falsetti, Via Tirandi, 13-scala F, 25128 Brescia, Italy) Abstract This study has evaluated the behaviour of 3a-androstanediol glucuronide (3a-diol G) in 170 women of whom 85 had polycystic ovary syndrome (PCOS), 35 had idiopathic hirsutism (IH) and 50 had regular cycles (control group). Of the women with PCOS, 45 were hirsute (PCOS-H) and 40 were non hirsute (PCOS-NH). Women in the control group were not hirsute. Hirsutism was assessed by the same physician using the Ferriman-Gallway score. The body mass index (BMI) was estimated in all of the women. Plasma concentrations of 3a-diol G were elevated only in hirsute patients, both with PCOS and with IH. Even in PCOS-NH, concentrations of 3a-diol G were higher compared with controls (P<0.001), but significantly lower (P < 0.001) than those of the PCOS-H and of the IH groups. The behaviour of 3a- diol G was not affected by BMI. European Journal of Endocrinology 138 421–424 Introduction The aim of our study is to provide further contri- butions to the clinical activity of 3a-diol G by evaluat- Hirsutism, affecting 5–8% of the whole female popula- ing its behaviour in a broad series of normal and tion of fertile age, is an important clinical and hyperandrogenic women, with and without hirsutism. -
New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies
molecules Article New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies Catarina Canário 1 , Mariana Matias 1, Vanessa Brito 1, Adriana O. Santos 1, Amílcar Falcão 2,3 , Samuel Silvestre 1,4,* and Gilberto Alves 1 1 CICS-UBI–Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal; [email protected] (C.C.); [email protected] (M.M.); [email protected] (V.B.); [email protected] (A.O.S.); [email protected] (G.A.) 2 Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; [email protected] 3 CIBIT-Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, 3000-548 Coimbra, Portugal 4 CNC–Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal * Correspondence: [email protected] Abstract: The interest in the introduction of the oxime group in molecules aiming to improve their biological effects is increasing. This work aimed to develop new steroidal oximes of the estrane series with potential antitumor interest. For this, several oximes were synthesized by reaction of hydroxylamine with the 17-ketone of estrone derivatives. Then, their cytotoxicity was evaluated in six cell lines. An estrogenicity assay, a cell cycle distribution analysis and a fluorescence microscopy study with Hoechst 3358 staining were performed with the most promising compound. In addition, molecular docking studies against estrogen receptor α, steroid sulfatase, 17β-hydroxysteroid dehy- drogenase type 1 and β-tubulin were also accomplished. The 2-nitroestrone oxime showed higher Citation: Canário, C.; Matias, M.; Brito, V.; Santos, A.O.; Falcão, A.; cytotoxicity than the parent compound on MCF-7 cancer cells. -
Neuroactive Steroids and Affective Symptoms in Women Across the Weight Spectrum
Neuropsychopharmacology (2018) 43, 1436–1444 © 2018 American College of Neuropsychopharmacology. All rights reserved 0893-133X/18 www.neuropsychopharmacology.org Neuroactive Steroids and Affective Symptoms in Women Across the Weight Spectrum ,1 1 1 2 2 Laura E Dichtel* , Elizabeth A Lawson , Melanie Schorr , Erinne Meenaghan , Margaret Lederfine Paskal , 3 4 4 5,6 1 Kamryn T Eddy , Graziano Pinna , Marianela Nelson , Ann M Rasmusson , Anne Klibanski and 1 Karen K Miller 1 2 Neuroendocrine Unit, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA; Neuroendocrine Unit, Massachusetts General 3 Hospital, Boston, MA, USA; Eating Disorders Clinical and Research Program, Massachusetts General Hospital/Harvard Medical School, Boston, 4 5 MA, USA; The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA; National Center for PTSD, Department of Veterans Affairs, VA Boston Healthcare System, Boston, MA, USA; 6Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA α α α α β 3 -5 -Tetrahydroprogesterone, a progesterone metabolite also known as allopregnanolone, and 5 -androstane-3 ,17 -diol, a α testosterone metabolite also known as 3 -androstanediol, are neuroactive steroids and positive GABAA receptor allosteric modulators. Both anorexia nervosa (AN) and obesity are complicated by affective comorbidities and hypothalamic–pituitary–gonadal dysregulation. However, it is not known whether neuroactive steroid levels are abnormal at the extremes of the weight spectrum. We hypothesized that serum allopregnanolone and 3α-androstanediol levels would be decreased in AN compared with healthy controls (HC) and negatively associated with affective symptoms throughout the weight spectrum, independent of body mass index (BMI). Thirty-six women were 1 : 1 age-matched across three groups: AN, HC, and overweight/obese (OW/OB). -
Public Law 108–358 108Th Congress An
PUBLIC LAW 108–358—OCT. 22, 2004 118 STAT. 1661 Public Law 108–358 108th Congress An Act To amend the Controlled Substances Act to clarify the definition of anabolic steroids and to provide for research and education activities relating to steroids and Oct. 22, 2004 steroid precursors. [S. 2195] Be it enacted by the Senate and House of Representatives of the United States of America in Congress assembled, Anabolic Steroid Control Act of SECTION 1. SHORT TITLE. 2004. This Act may be cited as the ‘‘Anabolic Steroid Control Act 21 USC 801 note. of 2004’’. SEC. 2. AMENDMENTS TO THE CONTROLLED SUBSTANCES ACT. (a) DEFINITIONS.—Section 102 of the Controlled Substances Act (21 U.S.C. 802) is amended— (1) in paragraph (41)— (A) by realigning the margin so as to align with para- graph (40); and (B) by striking subparagraph (A) and inserting the following: ‘‘(A) The term ‘anabolic steroid’ means any drug or hormonal substance, chemically and pharmacologically related to testosterone (other than estrogens, progestins, corticosteroids, and dehydroepiandrosterone), and includes— ‘‘(i) androstanediol— ‘‘(I) 3β,17β-dihydroxy-5α-androstane; and ‘‘(II) 3α,17β-dihydroxy-5α-androstane; ‘‘(ii) androstanedione (5α-androstan-3,17-dione); ‘‘(iii) androstenediol— ‘‘(I) 1-androstenediol (3β,17β-dihydroxy-5α-androst-1- ene); ‘‘(II) 1-androstenediol (3α,17β-dihydroxy-5α-androst-1- ene); ‘‘(III) 4-androstenediol (3β,17β-dihydroxy-androst-4- ene); and ‘‘(IV) 5-androstenediol (3β,17β-dihydroxy-androst-5- ene); ‘‘(iv) androstenedione— ‘‘(I) 1-androstenedione ([5α]-androst-1-en-3,17-dione); ‘‘(II) 4-androstenedione (androst-4-en-3,17-dione); and ‘‘(III) 5-androstenedione (androst-5-en-3,17-dione); ‘‘(v) bolasterone (7α,17α-dimethyl-17β-hydroxyandrost-4-en- 3-one); ‘‘(vi) boldenone (17β-hydroxyandrost-1,4,-diene-3-one); ‘‘(vii) calusterone (7β,17α-dimethyl-17β-hydroxyandrost-4- en-3-one); VerDate 11-MAY-2000 04:00 Nov 19, 2004 Jkt 039139 PO 00358 Frm 00001 Fmt 6580 Sfmt 6581 E:\PUBLAW\PUBL358.108 BILLW PsN: PUBL358 118 STAT.