Interaction of Methoxychlor and Related Compounds with Estrogen Receptor α and β, and Androgen Receptor: Structure-Activity Studies

  1. Kevin W. Gaido1,
  2. Susan C. Maness1,
  3. Donald P. McDonnell2,
  4. Shangara S. Dehal3,
  5. David Kupfer3 and
  6. Stephen Safe4
  1. 1Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina (K.W.G., S.C.M.); 2Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina (D.P.M.); 3Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts (S.S.D., D.K.); and 4Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (S.S.)

    Abstract

    We previously demonstrated differential interactions of the methoxychlor metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE) with estrogen receptor α (ERα), ERβ, and the androgen receptor (AR). In this study, we characterize the ERα, ERβ, and AR activity of structurally related methoxychlor metabolites. Human hepatoma cells (HepG2) were transiently transfected with human ERα, ERβ, and AR plus an appropriate steroid-responsive luciferase reporter vector. After transfection, cells were treated with various concentrations of HPTE or structurally related compounds in the presence (for detecting antagonism) and absence (for detecting agonism) of 17β-estradiol and dihydrotestosterone. The monohydroxy analog of methoxychlor, as well as monohydroxy and dihydroxy analogs of 2,2-bis(p-hydroxyphenyl)-1,1-dichloroethylene, had ERα agonist activity and ERβ and AR antagonist activity similar to HPTE. The trihydroxy metabolite of methoxychlor displayed only weak ERα agonist activity and did not alter ERβ or AR activities. Replacement of the trichloroethane or dichloroethylene group with a methyl group resulted in a compound with ERα and ERβ agonist activity that retained antiandrogenic activities. This study identifies some of the structural requirements for ERα and ERβ activity and demonstrates the complexity involved in determining the mechanism of action of endocrine-active chemicals that simultaneously act as agonists or antagonists through one or more hormone receptors.

    Footnotes

    • Send reprint requests to: Dr. Kevin W. Gaido, CIIT, P.O. Box 12137, Research Triangle Park, NC 27709. E-mail:gaido{at}ciit.org

    • The financial assistance of the National Institutes of Health (ES000834, ES09106, and ES04917) and the Texas Agricultural Experiment Station is gratefully acknowledged.

    • Abbreviations:
      DDT
      dichlorodiphenyltrichloroethane
      ER
      estrogen receptor
      AR
      androgen receptor
      TLC
      thin-layer chromatography
      E2
      17β-estradiol
      GC-MS
      gas chromatography-mass spectrometry
      p,p′-DDE
      2,2-bis(p-hydroxyphenyl)-1,1-dichloroethylene
      C3
      complement 3
      Luc
      luciferase
      CMV
      cytomegalovirus
      CPRG
      chlorophenol red-β-D-galactopyranoside
      HPTE
      2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane
      DHT
      dihydrotestosterone
      THC
      tetrahydrochrysene
      • Received March 10, 2000.
      • Accepted June 15, 2000.
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    1. Molecular Pharmacology October 1, 2000 vol. 58 no. 4 852-858
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