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

We previously demonstrated differential interactions of the methoxychlor me tabolite 2,2- bis(p-hydroxyphenyl)-1,1,1-trichloroethane(HPTE) with estroge n receptor alpha (ER alpha), ER beta, and the androgen receptor (AR). In th is study, we characterize the ER alpha, ER beta, and AR activity of structu rally related methoxychlor metabolites. Human hepatoma cells (HepG2) were t ransiently transfected with human ER alpha, ER beta, and AR plus an appropr iate steroid-responsive luciferase reporter vector. After transfection, cel ls were treated with various concentrations of HPTE or structurally related compounds in the presence (for detecting antagonism) and absence (for dete cting agonism) of 17 beta-estradiol and dihydrotestosterone. The monohydrox y analog of methoxychlor, as well as monohydroxy and dihydroxy analogs of 2 ,2- bis(p-hydroxyphenyl)-1,1-dichloroethylene, had ER alpha agonist activit y and ER beta and AR antagonist activity similar to HPTE. The trihydroxy me tabolite of methoxychlor displayed only weak ER alpha agonist activity and did not alter ER beta or AR activities. Replacement of the trichloroethane or dichloroethylene group with a methyl group resulted in a compound with E R alpha and ER beta agonist activity that retained antiandrogenic activitie s. This study identifies some of the structural requirements for ER alpha a nd ER beta 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.