title: Enantioselective recognition of mono-demethylated methoxychlor metabolites by the estrogen receptor.
abstract: Metabolites of methoxychlor such as 2-(p-hydroxyphenyl)-2-(p-methoxyphenyl)-1,1,1-trichloroethane (mono-OH-MXC) and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (bis-OH-MXC), have estrogenic activity. Mono-OH-MXC is a chiral compound in which the carbon atom bridging two benzene rings is the chiral centre. In previous studies the estrogenic activity of racemic mono-OH-MXC has been measured, and the activity of each enantiomer of this compound has not yet been elucidated. In this study, we evaluated the estrogen receptor-binding activity of each enantiomer of mono-OH-MXC to clarify the enantioselective recognition by the estrogen receptor. (S)-mono-OH-MXC showed 3-fold higher binding activity than that of the (R) enantiomer. The activity of bis-OH-MXC was only 1.7-fold higher than that of (S)-mono-OH-MXC. This result suggests that the one hydroxy group and the orientation of the CCl3 group of mono- and bis-OH-MXCs are important for the interaction with the estrogen receptor. The result also points out the estrogenic activity of methoxychlor after metabolic activation in vivo, which predominantly produces the (S)-mono-OH-MXC, may be higher than estimated from the in vitro activity of racemic mixtures.
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, 606-8502, Japan. miyamasa@kais.kyoto-u.ac.jp
authors.forename: Masahiro
authors.initials: M
authors.lastname: Miyashita
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shimada
authors.forename: Shizuka
authors.initials: S
authors.lastname: Nakagami
authors.forename: Norio
authors.initials: N
authors.lastname: Kurihara
authors.forename: Hisashi
authors.initials: H
authors.lastname: Miyagawa
authors.forename: Miki
authors.initials: M
authors.lastname: Akamatsu
mesh_terms: D004958:Estradiol / Q000737:chemistry / Q000378:metabolism; D008731:Methoxychlor / Q000737:chemistry / Q000378:metabolism*; D008745:Methylation; D011933:Reagent Kits, Diagnostic; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D011933:Reagent Kits, Diagnostic; D011960:Receptors, Estrogen; D004958:Estradiol; D008731:Methoxychlor