DOCSLIB.ORG

The Impact of Common Genetic Variations in Genes of the Sex Hormone Metabolic Pathways on Steroid Hormone Levels and Prostate Cancer Aggressiveness

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Impact of Common Genetic Variations in Genes of the Sex Hormone Metabolic Pathways on Steroid Hormone Levels and Prostate Cancer Aggressiveness Published OnlineFirst September 7, 2011; DOI: 10.1158/1940-6207.CAPR-11-0283 Cancer Prevention Research Article Research The Impact of Common Genetic Variations in Genes of the Sex Hormone Metabolic Pathways on Steroid Hormone Levels and Prostate Cancer Aggressiveness Tong Sun1, William K. Oh1, Susanna Jacobus2, Meredith Regan2, Mark Pomerantz1, Matthew L. Freedman1, Gwo-Shu Mary Lee1, and Philip W. Kantoff1 Abstract Our previous work suggested that there was no significant association between plasma steroid hormone levels and prostate cancer tumor grade at diagnosis. In this study, we systematically tested the hypothesis that inherited variations in the androgen and estrogen metabolic pathways may be associated with plasma levels of steroid hormones, or prostate cancer aggressiveness at diagnosis. Plasma hormone levels including total testosterone, total estradiol, and sex hormone–binding globulin were measured in a cohort of 508 patients identified with localized prostate cancer. D’Amico risk classification at diagnosis was also determined. A total of 143 single-nucleotide poly- morphisms (SNPs) from 30 genes that are involvedinandrogenandestrogenmetabolismwere selected for analysis. The global association of genotypes with plasma hormone levels and prostate cancer aggressiveness (D’Amico risk classification) was statistically analyzed. Q values were estimated to account for multiple testing. We observed significant associations between plasma testosterone level and SNPs in HSD17B2 (rs1424151), HSD17B3 (rs9409407), and HSD17B1 (rs12602084), with P values of 0.002, 0.006, and 0.006, respectively. We also observed borderline significant associations between prostate aggressiveness at diagnosis and SNPs in AKR1C1 (rs11252845; P ¼ 0.005), UGT2B15 (rs2045100; P ¼ 0.007), and HSD17B12 (rs7932905; P ¼ 0.008). No individual SNP was associated with both clinical variables. Genetic variants of genes in hormone metabolic pathways may influence plasma androgen levels or prostate cancer aggressiveness. However, it seems that the inherited variations affecting plasma hormone levels differ from those affecting disease aggressiveness. Cancer Prev Res; 4(12); 2044–50. Ó2011 AACR. Introduction principal androgen present in the blood, mostly bound to sex hormone–binding globulin (SHBG) and albumin. Sex steroid hormones influence the development, matu- Intracellularly, testosterone is enzymatically converted to ration, and maintenance of the prostate, affecting both the the more potent metabolite dihydrotestosterone (DHT). proliferation and differentiation status of the luminal epi- The complex of androgen (testosterone or DHT) and andro- thelium (1–3). Androgens are synthesized primarily in the gen receptor regulates the expression of a variety of genes testes or adrenal glands, and secondarily in peripheral that are involved in the growth, survival, and differentiation tissues including the prostate (2). Testosterone is the of prostate cells by binding to androgen response elements present in the regulatory regions of these genes (2). The relationship between androgens and the develop- Authors' Affiliations: Departments of 1Medical Oncology and 2Biostatis- ment of prostate cancer is complex. Some early studies tics and Computational Biology, Dana-Farber Cancer Institute and Harvard showed that plasma testosterone levels might be correlated Medical School, Boston, Massachusetts with Gleason grade or time to progression after orchiectomy Note: Supplementary data for this article are available at Cancer Prevention of prostate cancer (3, 4). However, other studies indicated Research Online (http://cancerprevres.aacrjournals.org/). no evidence of any association between plasma testoster- Current address for W.K. Oh: Department of Medical Oncology, Mount one, estradiol (E2), and SHBG with Gleason score at the Sinai School of Medicine, New York, NY 10029, USA. time of diagnosis (5, 6). Thus, there is insufficient evidence Corresponding Authors: Gwo-Shu Mary Lee or Philip W. Kantoff, Depart- to support the hypothesis that higher blood levels of steroid ment of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave. Binney Street, Boston, MA 02215. Phone: 617-632-1914; Fax: 617- hormones are associated with prostate cancer development 632-2165; E-mail: [email protected]; and Philip W. Kantoff, or progression. One explanation for this lack of association [email protected] is the uncertain correlation between the plasma concentra- doi: 10.1158/1940-6207.CAPR-11-0283 tions of androgens with the intraprostatic hormone levels, Ó2011 American Association for Cancer Research. an essential component in the tumor microenvironment 2044 Cancer Prev Res; 4(12) December 2011 Downloaded from cancerpreventionresearch.aacrjournals.org on September 24, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst September 7, 2011; DOI: 10.1158/1940-6207.CAPR-11-0283 Genetic Polymorphisms, Steroid Hormone, and Prostate Cancer Aggressiveness that potentially affects tumor growth (2, 7, 8). Another testosterone levels in Caucasian men in both cases and explanation is that a single determination of plasma andro- controls. They also identified relating SNPs in ESR1 and gens in middle or older age may not be representative of SRD5A2 with testosterone and 3a-androstanediol-glucu- time-averaged or maximum levels over the etiologically ronide, respectively (19). relevant time of life (9). Similarly, the relationship between We present here a systematic analysis of 143 common estrogen levels and prostate cancer is unclear. There is some polymorphisms in 30 genes that are involved in the sex evidence that estrogen metabolites functioning as genotox- steroid hormones metabolic pathways for their potential ins can increase risk for prostate cancer (10). It also has been associations with plasma total testosterone, total estradiol, suggested that a decrease in the androgen/estrogen ratio and SHBG, or with prostate cancer aggressiveness in an with aging could be responsible in part for prostate carci- established cohort of 508 patients with newly diagnosed nogenesis (10). localized prostate cancer. Therapeutically, blocking androgen production has been one of the most commonly used treatments of advanced Materials and Methods prostate cancer and is often successful until castration resistant growth is acquired (2, 11, 12). In addition, estro- Study population and laboratory assays gens are recognized therapies for prostate cancer. Oral E2 The study cohort and the measurement of hormone levels administration may be useful for treatment of advanced have been previously described in detail (5, 20). Briefly, a castration-resistant prostate cancer (10). This therapy also total of 539 patients with localized prostate cancer evalu- has side effects and that the effects of estrogens are mediated ated at the Dana-Farber Cancer Institute from 2001 to 2005, by 2 different receptors, estrogen receptor a (ERa) and ERb who were enrolled in a prospective sample banking proto- (10). col, were eligible for this study. Most clinical data were Genetic polymorphisms of genes involved in metabolic abstracted from the Current Research Information System pathways of sex steroid hormones have been investigated database, as described (21). Because mixed ethnicity could as candidates for prostate cancer risk in many association confound the association results, we removed 31 patients of studies (13–16). Data from these case–control studies non-Caucasian race or with indeterminate ancestry from suggest that interindividual variation in genes involved this study. A total of 508 individuals were analyzed. These in sex hormone metabolic pathway could be related to the individuals either self-reported as European American or risk of prostate cancer incidence (13–16). However, few were determined to be of European ancestry, based on studies have examined the association of these poly- genotyping of ancestry informative markers. Using the morphisms with blood hormone levels in prostate cancer D’Amico risk classification criteria, newly diagnosed (17–19). In the National Cancer Institute (NCI)-Breast patients with prostate cancer were classified as at low, and Prostate Cancer Cohort Consortium (BPC3) study, intermediate, or high risk of clinical recurrence after pri- single-nucleotide polymorphisms (SNP) in SHBG gene mary therapy (22). Briefly, 3 risk groups were established on werefoundtobeassociatedwithcirculatingSHBGand the basis of serum prostate-specific antigen (PSA) level, HSD17B1, HSD17B7 Cholesterol DHEA-S HSD17B2 Androstenediol-S CYP11A1 SULT2A1 STS SULT1E1 STS AKR1C3 3β-Androstanediol CYP17A1 Pregnenolone DHEA Androstenediol HSD17B2 HSD3B1, HSD3B2 HSD3B1, HSD3B2 HSD3B1, HSD3B2 AKR1C1 AKR1C3, HSD17B1 AKR1C1, AKR1C2 CYP17A1 HSD17B3, HSD17B7 SRD5A1, SRD5A2 AKR1C3, AKR1C4 Progesterone Androstenedione Testosterone DHT 3α-Androstanediol AKR1C3, HSD17B2 HSD17B HSD17B4 UGT2B15 UGT2B15 CYP19A1 CYP19A1 UGT2B17 UGT2B17 AKR1C3, HSD17B1 UGT2B4 UGT2B4 HSD17B7, HSD17B12 β Estrone 17 -Estradiol DHT-17-glucuronide 3α-Androstanediol- HSD17B2 17-glucuronide CYP3A4, CYP1A1 UGT2B28 SULT1A1 UGT2B4 SULT1E1, SULT2A1 UGT2B7 4-Hydroxyestron 17β-Estra-1,3,5-trien 3,17-diol Estradiol 3-glucuronide 3-sulfate COMT CYP3A4, CYP1A1, CYP1B1 Methoxyestrone Hydroxyestradiol COMT Methoxyestradiol Figure 1. Candidate genes involved in androgen and estrogen biosynthesis and metabolism process. This diagram shows how the 30 metabolic genes analyzed in this study are involved in different steps of androgen
Load more

Recommended publications
  • Association Between CYP17A1, CYP19A1, and HSD17B1 Gene Polymorphisms in Hormone Synthesis Pathway with Ovarian Cancer Risk
    Association between CYP17A1, CYP19A1, and HSD17B1 Gene Polymorphisms in Hormone Synthesis pathway with Ovarian Cancer Risk Gowtham Kumar G1, Andrea Francis1, Solomon Paul1, Chirag Molia1, Manickavasagam M1, Usha Rani1, Ramya R1, and Nalini Ganesan1 1Sri Ramachandra Institute of Higher Education and Research August 27, 2020 Abstract Objective: To investigate the polymorphisms of genes in the steroidogenesis pathway to understand the etiological mechanisms to OC risk in the South Indian population Design: Case-Control Study Setting and Sample: Ovarian cancer cases (200) and healthy individuals (200) from the South Indian population. Methods: All the cases and controls were genotyped for SNPs by using allelic discrimination assay. Main outcome measures: Genetic distribution of SNPs of Steroidogenesis pathway genes in the South Indian population. Results: The observed results for rs743752, the homozygous CC genotype revealed significant association (OR; 1.68; 95%CI, 1.25-2.26; p =<0.05) and the dominant model, recessive model and additive model showed a significant association with an OR of 1.62; 95%CI, 1.09 { 2.42; p = 0.015, OR of 0.29, 95%CI, 0.14 { 0.60; p = <0.001 and OR of 1.68, 95%CI, 1.25 { 2.26); p = <0.001 respectively in cases and controls for OC risk. In rs10046, the heterozygous CT genotype (OR; 1.61; 95%CI 1.06 { 2.43; p = 0.023), the dominant (OR; 1.65; 95%CI, 1.11 { 2.45; p = 0.012) and the additive (OR; 1.46; 95%CI, 1.07 - 1.98; p = 0.015) models were found to be statistically significant.
    [Show full text]
  • Polymorphic Human Sulfotransferase 2A1 Mediates the Formation of 25-Hydroxyvitamin
    Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2018/01/17/dmd.117.078428.DC1 1521-009X/46/4/367–379$35.00 https://doi.org/10.1124/dmd.117.078428 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 46:367–379, April 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Polymorphic Human Sulfotransferase 2A1 Mediates the Formation of 25-Hydroxyvitamin D3-3-O-Sulfate, a Major Circulating Vitamin D Metabolite in Humans s Timothy Wong, Zhican Wang, Brian D. Chapron, Mizuki Suzuki, Katrina G. Claw, Chunying Gao, Robert S. Foti, Bhagwat Prasad, Alenka Chapron, Justina Calamia, Amarjit Chaudhry, Erin G. Schuetz, Ronald L. Horst, Qingcheng Mao, Ian H. de Boer, Timothy A. Thornton, and Kenneth E. Thummel Departments of Pharmaceutics (T.W., Z.W., B.D.C., M.S., K.G.C., C.G., B.P., Al.C., J.C., Q.M., K.E.T.), Medicine and Kidney Research Institute (I.H.d.B.), and Biostatistics (T.A.T.), University of Washington, Seattle, Washington; Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, California (Z.W.); Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Cambridge, Massachusetts (R.S.F.); St. Jude Children’s Research Hospital, Memphis, Tennessee Downloaded from (Am.C., E.G.S.); and Heartland Assays LLC, Ames, Iowa (R.L.H.) Received September 1, 2017; accepted January 10, 2018 ABSTRACT dmd.aspetjournals.org Metabolism of 25-hydroxyvitamin D3 (25OHD3) plays a central role in with the rates of dehydroepiandrosterone sulfonation. Further analysis regulating the biologic effects of vitamin D in the body.
    [Show full text]
  • Transcriptomic Characterization of Fibrolamellar Hepatocellular
    Transcriptomic characterization of fibrolamellar PNAS PLUS hepatocellular carcinoma Elana P. Simona, Catherine A. Freijeb, Benjamin A. Farbera,c, Gadi Lalazara, David G. Darcya,c, Joshua N. Honeymana,c, Rachel Chiaroni-Clarkea, Brian D. Dilld, Henrik Molinad, Umesh K. Bhanote, Michael P. La Quagliac, Brad R. Rosenbergb,f, and Sanford M. Simona,1 aLaboratory of Cellular Biophysics, The Rockefeller University, New York, NY 10065; bPresidential Fellows Laboratory, The Rockefeller University, New York, NY 10065; cDivision of Pediatric Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; dProteomics Resource Center, The Rockefeller University, New York, NY 10065; ePathology Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; and fJohn C. Whitehead Presidential Fellows Program, The Rockefeller University, New York, NY 10065 Edited by Susan S. Taylor, University of California, San Diego, La Jolla, CA, and approved September 22, 2015 (received for review December 29, 2014) Fibrolamellar hepatocellular carcinoma (FLHCC) tumors all carry a exon of DNAJB1 and all but the first exon of PRKACA. This deletion of ∼400 kb in chromosome 19, resulting in a fusion of the produced a chimeric RNA transcript and a translated chimeric genes for the heat shock protein, DNAJ (Hsp40) homolog, subfam- protein that retains the full catalytic activity of wild-type PKA. ily B, member 1, DNAJB1, and the catalytic subunit of protein ki- This chimeric protein was found in 15 of 15 FLHCC patients nase A, PRKACA. The resulting chimeric transcript produces a (21) in the absence of any other recurrent mutations in the DNA fusion protein that retains kinase activity.
    [Show full text]
  • Chronic Exposure to Bisphenol a Reduces SULT1A1 Activity in the Human Placental Cell Line Bewo
    Chronic exposure to bisphenol A reduces SULT1A1 activity in the human placental cell line BeWo Pallabi Mitra Department of Pharmaceutical Chemistry University of Kansas October 27, 2006 Outline ▪ Placental structure and models ▪ Placental permeation ▪ Placental metabolism and regulation (induction/inhibition) ▪ Sulfotransferase enzymes in trophoblast ▪ Bisphenol A ▪ Effects of bisphenol A on SULT1A1 ▪ Conclusions The placental barrier The placental barrier Mother’s blood •Trophoblasts and syncytiotrophoblasts line the maternal villar surface in a monolayer- like fashion. •Constitute the rate limiting barrier to exchange between the maternal and fetal blood. Syme et al., Drug transfer and metabolism by the human placenta, Clin Pharmacokinet 2004: 43(8): 487-514 Models of the human placenta ▪ In vivo models – Anatomical and functional differences between mammalian placentas makes it difficult to extrapolate animal studies to humans. ▪ In vitro models ▪ Perfused placental cotyledon ▪ Isolated trophoblast plasma membrane ▪ Isolated transporters and receptors ▪ Villous explants ▪ Primary cultures (cytotrophoblasts) ▪ Immortalized cell lines (BeWo, JAr, JEG, HRP-1, etc.) Refn. Bode et al. In Vitro models for studying trophoblast transcellular transport, Methods Mol Med. 2006;122:225-39 Sastry, B.V., Adv Drug Deliv Rev., 1999 Jun 14. 38(1): p. 17-39. Placental permeation - Factors Efflux Carrier-mediated Passive diffusion transport Metabolism A A X A A Maternal side A X-OH A Fetal side Placental metabolism ▪ Though enzyme expression is much more restricted than hepatic metabolism, those that are functional metabolize xenobiotics as well as hormones. ▪ Placental enzymes CYP1A1/1A2, CYP19 (aromatase), GST, UGT, SULT ▪ Maternal blood-borne chemicals (drugs/polychlorinated biphenyls/pesticides) alter expression and activity. • Altered steroid metabolism.
    [Show full text]
  • Regulation of Xenobiotic and Bile Acid Metabolism by the Anti-Aging Intervention Calorie Restriction in Mice
    REGULATION OF XENOBIOTIC AND BILE ACID METABOLISM BY THE ANTI-AGING INTERVENTION CALORIE RESTRICTION IN MICE By Zidong Fu Submitted to the Graduate Degree Program in Pharmacology, Toxicology, and Therapeutics and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Dissertation Committee ________________________________ Chairperson: Curtis Klaassen, Ph.D. ________________________________ Udayan Apte, Ph.D. ________________________________ Wen-Xing Ding, Ph.D. ________________________________ Thomas Pazdernik, Ph.D. ________________________________ Hao Zhu, Ph.D. Date Defended: 04-11-2013 The Dissertation Committee for Zidong Fu certifies that this is the approved version of the following dissertation: REGULATION OF XENOBIOTIC AND BILE ACID METABOLISM BY THE ANTI-AGING INTERVENTION CALORIE RESTRICTION IN MICE ________________________________ Chairperson: Curtis Klaassen, Ph.D. Date approved: 04-11-2013 ii ABSTRACT Calorie restriction (CR), defined as reduced calorie intake without causing malnutrition, is the best-known intervention to increase life span and slow aging-related diseases in various species. However, current knowledge on the exact mechanisms of aging and how CR exerts its anti-aging effects is still inadequate. The detoxification theory of aging proposes that the up-regulation of xenobiotic processing genes (XPGs) involved in phase-I and phase-II xenobiotic metabolism as well as transport, which renders a wide spectrum of detoxification, is a longevity mechanism. Interestingly, bile acids (BAs), the metabolites of cholesterol, have recently been connected with longevity. Thus, this dissertation aimed to determine the regulation of xenobiotic and BA metabolism by the well-known anti-aging intervention CR. First, the mRNA expression of XPGs in liver during aging was investigated.
    [Show full text]
  • Hsd17b1) Inhibitor for Endometriosis
    DEVELOPMENT OF HYDROXYSTEROID (17-BETA) DEHYDROGENASE TYPE 1 (HSD17B1) INHIBITOR FOR ENDOMETRIOSIS Niina Saarinen1,2, Tero Linnanen1, Jasmin Tiala1, Camilla Stjernschantz1, Leena Hirvelä1, Taija Heinosalo2, Bert Delvoux3, Andrea Romano3, Gabriele Möller4, Jerzy Adamski4, Matti Poutanen2, Pasi Koskimies1 1Forendo Pharma Ltd, Finland; 2Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Finland; 3Department of Obstetrics and Gynaecology; GROW, School for Oncology and Developmental Biology; Maastricht University Medical Centre, The Netherlands; 4Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Germany BACKGROUND OBJECTIVE Local activation of estrogens in endometriosis tissue The main objective of the present work was to assess is considered important for growth of the lesions. the preclinical efficacy of the novel HSD17B1 inhibitor, Hydroxysteroid (17-beta) dehydrogenase type 1 FOR-6219 (HSD17B1) is expressed in endometriosis tissue and converts the biologically low-active estrogen, estrone (E1), to the highly active estradiol (E2), while hydroxysteroid (17-beta) dehydrogenase type 2 (HSD17B2), catalyzes the opposite reaction. In contrast to eutopic endometrium, in endometriotic lesions the HSD17B1/HSD17B2 expression ratio is increased and E2 levels are higher than those of E1 throughout the menstrual cycle. Thus, inhibition of HSD17B1 is considered as a feasible strategy for lowering local E2 production in endometriosis. MAIN RESULTS FOR-6219 inhibits human HSD17B1 Ø FOR-6219 is a potent and FOR-6219 does not trigger estrogenic fully selective inhibitor of response in immature rat uterine human HSD17B1 over growth assay HSD17B2 Ø FOR-6219 does not bind to estrogen receptor α or β, and exhibits no estrogen-like response in immature rat uterotrophic assay Ø FOR-6219 inhibits HSD17B1 in cynomolgus monkey, dog and rabbit i.e.
    [Show full text]
  • Identification of Human Sulfotransferases Involved in Lorcaserin N-Sulfamate Formation
    1521-009X/44/4/570–575$25.00 http://dx.doi.org/10.1124/dmd.115.067397 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 44:570–575, April 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Identification of Human Sulfotransferases Involved in Lorcaserin N-Sulfamate Formation Abu J. M. Sadeque, Safet Palamar,1 Khawja A. Usmani, Chuan Chen, Matthew A. Cerny,2 and Weichao G. Chen3 Department of Drug Metabolism and Pharmacokinetics, Arena Pharmaceuticals, Inc., San Diego, California Received September 30, 2015; accepted January 7, 2016 ABSTRACT Lorcaserin [(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benza- and among the SULT isoforms SULT1A1 was the most efficient. The zepine] hydrochloride hemihydrate, a selective serotonin 5-hydroxy- order of intrinsic clearance for lorcaserin N-sulfamate is SULT1A1 > Downloaded from tryptamine (5-HT) 5-HT2C receptor agonist, is approved by the U.S. SULT2A1 > SULT1A2 > SULT1E1. Inhibitory effects of lorcaserin Food and Drug Administration for chronic weight management. N-sulfamate on major human cytochrome P450 (P450) enzymes Lorcaserin is primarily cleared by metabolism, which involves were not observed or minimal. Lorcaserin N-sulfamate binds to multiple enzyme systems with various metabolic pathways in human plasma protein with high affinity (i.e., >99%). Thus, despite humans. The major circulating metabolite is lorcaserin N-sulfamate. being the major circulating metabolite, the level of free lorcaserin Both human liver and renal cytosols catalyze the formation of N-sulfamate would be minimal at a lorcaserin therapeutic dose and lorcaserin N-sulfamate, where the liver cytosol showed a higher unlikely be sufficient to cause drug-drug interactions.
    [Show full text]
  • Chuanxiong Rhizoma Compound on HIF-VEGF Pathway and Cerebral Ischemia-Reperfusion Injury’S Biological Network Based on Systematic Pharmacology
    ORIGINAL RESEARCH published: 25 June 2021 doi: 10.3389/fphar.2021.601846 Exploring the Regulatory Mechanism of Hedysarum Multijugum Maxim.-Chuanxiong Rhizoma Compound on HIF-VEGF Pathway and Cerebral Ischemia-Reperfusion Injury’s Biological Network Based on Systematic Pharmacology Kailin Yang 1†, Liuting Zeng 1†, Anqi Ge 2†, Yi Chen 1†, Shanshan Wang 1†, Xiaofei Zhu 1,3† and Jinwen Ge 1,4* Edited by: 1 Takashi Sato, Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of 2 Tokyo University of Pharmacy and Life Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China, Galactophore Department, The First 3 Sciences, Japan Hospital of Hunan University of Chinese Medicine, Changsha, China, School of Graduate, Central South University, Changsha, China, 4Shaoyang University, Shaoyang, China Reviewed by: Hui Zhao, Capital Medical University, China Background: Clinical research found that Hedysarum Multijugum Maxim.-Chuanxiong Maria Luisa Del Moral, fi University of Jaén, Spain Rhizoma Compound (HCC) has de nite curative effect on cerebral ischemic diseases, *Correspondence: such as ischemic stroke and cerebral ischemia-reperfusion injury (CIR). However, its Jinwen Ge mechanism for treating cerebral ischemia is still not fully explained. [email protected] †These authors share first authorship Methods: The traditional Chinese medicine related database were utilized to obtain the components of HCC. The Pharmmapper were used to predict HCC’s potential targets. Specialty section: The CIR genes were obtained from Genecards and OMIM and the protein-protein This article was submitted to interaction (PPI) data of HCC’s targets and IS genes were obtained from String Ethnopharmacology, a section of the journal database.
    [Show full text]
  • Molecular Genetic Markers Associated with Boar Taint – Could Molecular Genetics Contribute to Its Reduction?
    RESEARCH IN PIG BREEDING, 13, 2019 (1) REVIEW: MOLECULAR GENETIC MARKERS ASSOCIATED WITH BOAR TAINT – COULD MOLECULAR GENETICS CONTRIBUTE TO ITS REDUCTION? Falková L. and Vrtková I. Laboratory of Agrogenomics, Department of Animal Morphology, Physiology and Genetics, Mendel University in Brno, Czech Republic Abstract Boar taint is an unpleasant meat odour or taste occurring in uncastrated male pigs usually. Naturally occurring compounds – androstenone, skatole and indole – and their accumulation in the adipose tissue of entire boars cause the perceptible boar taint. Individual levels or combination of these compounds lead to perception of boar taint observed during culinary process and pork consumption. The ban on surgical castration based on EU legislation makes it necessary to find a solution that enables our producers to adapt to these new conditions and ensure their competitiveness. Alternative options include the use of molecular genetic markers that affect the levels of androstenone and skatole in pig adipose tissue by Marker Assisted Selection (MAS). The aim of this review is to provide overview in recent facts in the field of molecular genetics and possibility in boar taint reduction solution. Key Words: Boar taint, genomic markers, selection Boar taint degree while in the skatole level besides genetic Boar taint is an unpleasant odour or taste of and age factor the nutrition and environmental meat from entire male pigs. The occurrence in factors play key role (Zamartskaia and Squires, adult pig males is connected with the hormone 2009). Skatole occurs in both male and female changes during maturation (Duijvesteijn et al., pigs but in male ones three times more (Wesoly 2010).
    [Show full text]
  • Dottorato Di Ricerca the Effect of Finasteride
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by UniCA Eprints Università degli Studi di Cagliari DOTTORATO DI RICERCA Scuola di Dottorato in Neuroscienze e Scienze Morfologiche Corso di Dottorato in Neuroscienze Ciclo XXIII THE EFFECT OF FINASTERIDE IN TOURETTE SYNDROME: RESULTS OF A CLINICAL TRIAL Settore scientifico disciplinari di afferenza BIO/14 Presentata da: Silvia Paba Coordinatore Dottorato Prof.ssa Alessandra Concas Tutor Dott.ssa Paola Devoto Esame finale anno accademico 2009 - 2010 1. INTRODUCTION 1 1.1 General characteristics of steroid 5α-reductase 2 1.2 S5αR inhibitors 15 1.3 S5αR inhibitors as putative therapeutic agents for some neuropsychiatric disorders. 23 2. AIMS OF THE STUDY 37 3. METHODS 38 3.1 Subjects 38 3.2 Procedures 39 3.3 Data analysis 40 4. RESULTS 41 4.1 Description of sample 41 4.2 Dosing, range and compliance 41 4.3 Effects of finasteride on TS and tic severity 44 4.4 Effects of finasteride on obsessive compulsive symptoms 46 4.5 Adverse effects 47 5. DISCUSSION 48 6. CONCLUSION 52 REFERENCES 54 1. INTRODUCTION The enzyme steroid 5α reductase (S5αR) catalyzes the conversion of Δ4-3-ketosteroid precursors - such as testosterone, progesterone and androstenedione - into their 5α- reduced metabolites. Although the current nomenclature assigns five enzymes to the S5αR family, only the types 1 and 2 appear to play an important role in steroidogenesis, mediating an overlapping set of reactions, albeit with distinct chemical characteristics and anatomical distribution. The discovery that the 5α-reduced metabolite of testosterone, 5α-dihydrotestosterone (DHT), is the most potent androgen and stimulates prostatic growth led to the development of S5αR inhibitors with high efficacy and tolerability.
    [Show full text]
  • Estrogen-Metabolizing Gene Polymorphisms in the Assessment of Female Hormone-Dependent Cancer Risk
    The Pharmacogenomics Journal (2006) 6, 189–193 & 2006 Nature Publishing Group All rights reserved 1470-269X/06 $30.00 www.nature.com/tpj ORIGINAL ARTICLE Estrogen-metabolizing gene polymorphisms in the assessment of female hormone-dependent cancer risk ON Mikhailova1, LF Gulyaeva1, Allelic variants of cytochrome P450: CYP1A1, CYP1A2, CYP19 (Aromatase) 1 2 and II-phase enzyme Sulfotransferase (SULT1A1) genes are associated with a AV Prudnikov , AV Gerasimov high risk of hormone-dependent cancers. We estimated a frequency of these 2 and SE Krasilnikov allelic variants in the female Caucasian population of the Novosibirsk region of Russia and their association with the elevated risk of ovarian and 1Institute of Molecular Biology and Biophysics, Novosibirsk, Russia and 2Regional Clinical endometrial cancer. A DNA bank of gynecologic oncology patients, patients Oncological Hospital, Novosibirsk, Russia with benign gynecologic diseases and healthy women was created, and the following single nucleotide polymorphisms (SNPs) were examined: CYP1A1 Correspondence: M1 polymorphism, that is, T264-C transition in the 30-noncoding region; Dr ON Mikhailova, Department of Molecular CYP1A2*1F polymorphism, that is, C734-A transversion in CYP1A2 gene; Mechanisms of Carcinogenesis, Institute of - Molecular Biology and Biophysics, Siberian C T transition (Arg264Cys) in exon 7 of CYP19; SULT1A1*2 polymorphism, Branch of the Russian Academy of Medical that is, G638-A transition (Arg213His) in SULT1A1 gene. A positive Sciences, Timakov Str. 2, Novosibirsk, correlation of C allele of CYP1A2*1F and G allele of SULT1A1*2 with 630117, Russia. hormone-dependent cancers in women was found. Thus, these genes are E-mail: [email protected] appropriate candidates for studying the contribution of genetic factors to endocrine disorder and environmentally determined diseases susceptibility.
    [Show full text]
  • Insights Into Steroid Sulfation and Desulfation Pathways
    61 2 Journal of Molecular P A Foster and J W Mueller Steroid sulfation 61:2 T271–T283 Endocrinology THEMATIC REVIEW SULFATION PATHWAYS Insights into steroid sulfation and desulfation pathways Paul A Foster1,2 and Jonathan Wolf Mueller1,2 1Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UK 2Centre for Endocrinology, Diabetes and Metabolism (CEDAM), Birmingham Health Partners, Birmingham, UK Correspondence should be addressed to J W Mueller: [email protected] or to P A Foster: [email protected] This paper is part of a thematic section on Sulfation Pathways. The guest editors for this section were Jonathan Wolf Mueller and Paul Foster. They were not involved in the peer review of this paper on which they are listed as authors and it was handled by another member of the journal’s Editorial board. Abstract Sulfation and desulfation pathways represent highly dynamic ways of shuttling, Key Words repressing and re-activating steroid hormones, thus controlling their immense biological f adrenal hormones potency at the very heart of endocrinology. This theme currently experiences growing f androgens research interest from various sides, including, but not limited to, novel insights about f DHEA phospho-adenosine-5′-phosphosulfate synthase and sulfotransferase function and f hormone action regulation, novel analytics for steroid conjugate detection and quantification. Within f steroid homones this review, we will also define how sulfation pathways are ripe for drug development strategies, which have translational potential to treat a number of conditions, including Journal of Molecular chronic inflammatory diseases and steroid-dependent cancers.
    [Show full text]