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Interaction of methoxychlor and related compounds with estrogen receptor alpha and beta, and androgen receptor: structure-activity studies.

Publication ,  Journal Article
Gaido, KW; Maness, SC; McDonnell, DP; Dehal, SS; Kupfer, D; Safe, S
Published in: Mol Pharmacol
October 2000

We previously demonstrated differential interactions of the methoxychlor metabolite 2,2-bis(p-hydroxyphenyl)-1,1, 1-trichloroethane (HPTE) with estrogen receptor alpha (ERalpha), ERbeta, and the androgen receptor (AR). In this study, we characterize the ERalpha, ERbeta, and AR activity of structurally related methoxychlor metabolites. Human hepatoma cells (HepG2) were transiently transfected with human ERalpha, ERbeta, 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 17beta-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 ERalpha agonist activity and ERbeta and AR antagonist activity similar to HPTE. The trihydroxy metabolite of methoxychlor displayed only weak ERalpha agonist activity and did not alter ERbeta or AR activities. Replacement of the trichloroethane or dichloroethylene group with a methyl group resulted in a compound with ERalpha and ERbeta agonist activity that retained antiandrogenic activities. This study identifies some of the structural requirements for ERalpha and ERbeta 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.

Duke Scholars

Published In

Mol Pharmacol

ISSN

0026-895X

Publication Date

October 2000

Volume

58

Issue

4

Start / End Page

852 / 858

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transfection
  • Structure-Activity Relationship
  • Receptors, Estrogen
  • Receptors, Androgen
  • Phenols
  • Pharmacology & Pharmacy
  • Methoxychlor
  • Insecticides
  • Humans
 

Citation

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Gaido, K. W., Maness, S. C., McDonnell, D. P., Dehal, S. S., Kupfer, D., & Safe, S. (2000). Interaction of methoxychlor and related compounds with estrogen receptor alpha and beta, and androgen receptor: structure-activity studies. Mol Pharmacol, 58(4), 852–858.
Gaido, K. W., S. C. Maness, D. P. McDonnell, S. S. Dehal, D. Kupfer, and S. Safe. “Interaction of methoxychlor and related compounds with estrogen receptor alpha and beta, and androgen receptor: structure-activity studies.Mol Pharmacol 58, no. 4 (October 2000): 852–58.
Gaido KW, Maness SC, McDonnell DP, Dehal SS, Kupfer D, Safe S. Interaction of methoxychlor and related compounds with estrogen receptor alpha and beta, and androgen receptor: structure-activity studies. Mol Pharmacol. 2000 Oct;58(4):852–8.
Gaido KW, Maness SC, McDonnell DP, Dehal SS, Kupfer D, Safe S. Interaction of methoxychlor and related compounds with estrogen receptor alpha and beta, and androgen receptor: structure-activity studies. Mol Pharmacol. 2000 Oct;58(4):852–858.

Published In

Mol Pharmacol

ISSN

0026-895X

Publication Date

October 2000

Volume

58

Issue

4

Start / End Page

852 / 858

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transfection
  • Structure-Activity Relationship
  • Receptors, Estrogen
  • Receptors, Androgen
  • Phenols
  • Pharmacology & Pharmacy
  • Methoxychlor
  • Insecticides
  • Humans