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

Abstract

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.

An exploration of the estrogen receptor transcription activity of capsaicin analogues via an integrated approach based on in silico prediction and in vitro assays

“…Thus, 6-I-CPS binding may need more entropy compensation for induced fit conformational change. Similarly, the small sized molecule HPTE of 194.35 cm 3 /mol was also located in the agonist area, which complied with the reports of Gaido and Freyberger (Gaido et al, 1999(Gaido et al, , 2000Freyberger and Schmuck, 2005).…”

Glucuronidation and sulfonation, in vitro, of the major endocrine-active metabolites of methoxychlor in the channel catfish, Ictalurus punctatus, and induction following treatment with 3-methylcholanthrene

“…MXC metabolism by P450 isoforms both in vitro and in vivo have led to the identification of two major metabolites, formed by its sequential demethylation: the chiral mono-demethylated 2-(p-hydroxyphenyl)-2-(p-methoxyphenyl)-1,1,1-trichloroethane (OH-MXC) and the bis-demethylated 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE) (Figure 1). MXC itself has negligible estrogenic activity in mammals, however both metabolites have been shown to interact with human estrogen and androgen receptors, HPTE being more potent than OHMXC (Kupfer and Bulger, 1987;Gaido et al, 1999;Gaido et al, 2000;Miyashita et al, 2004). Exposure of fish to MXC has been shown to induce vitellogenin synthesis (Schlenk et al, 1998;Hemmer et al, 2001) and affect development (Krisfalusi et al, 1998).…”

Early postnatal methoxychlor exposure inhibits folliculogenesis and stimulates anti-Mullerian hormone production in the rat ovary

“…One of the primary metabolites of MXC is 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). HPTE shows estrogenic, anti-estrogenic, or anti-androgenic activities depending on the receptor subtype (Maness et al 1998, Gaido et al 2000. MXC is considered to be a model endocrine disruptor (Cummings 1997) with direct effects on the antral follicle (Miller et al 2005).…”