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Vol. 58, Issue 4, 852-858, October 2000
and 
, and Androgen Receptor: Structure-Activity Studies
Chemical Industry Institute of Toxicology, Research Triangle Park,
North Carolina (K.W.G., S.C.M.); Department of Pharmacology and Cancer
Biology, Duke University Medical Center, Durham, North Carolina
(D.P.M.); Department of Pharmacology and Molecular Toxicology,
University of Massachusetts Medical Center, Worcester, Massachusetts
(S.S.D., D.K.); and Department of Veterinary Physiology and
Pharmacology, Texas A&M University, College Station, Texas (S.S.)
We previously demonstrated differential interactions of the
methoxychlor metabolite
2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE)
with estrogen receptor 
(ER), ER
, and the androgen receptor (AR). In this study, we characterize the ER, ER, and AR activity of structurally related methoxychlor metabolites. Human hepatoma cells
(HepG2) were transiently transfected with human ER, ER, 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 17-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 ER
agonist activity and ER and AR antagonist activity similar to HPTE.
The trihydroxy metabolite of methoxychlor displayed only weak ER
agonist activity and did not alter ER or AR activities. Replacement
of the trichloroethane or dichloroethylene group with a methyl group
resulted in a compound with ER and ER agonist activity that
retained antiandrogenic activities. This study identifies some of the
structural requirements for ER and ER 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.
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