Enantioselective recognition of mono-demethylated methoxychlor metabolites by the estrogen receptor.
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.
Miyashita
Masahiro
M
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, 606-8502, Japan. miyamasa@kais.kyoto-u.ac.jp
Shimada
Takahiro
T
Nakagami
Shizuka
S
Kurihara
Norio
N
Miyagawa
Hisashi
H
Akamatsu
Miki
M
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
D011933:Reagent Kits, Diagnostic; D011960:Receptors, Estrogen; D004958:Estradiol; D008731:Methoxychlor