Structural essentials of xenoestrogen dialkyl phthalates to bind to the estrogen receptors.
Xenoestrogen dialkyl phthalates, C(6)H(4)(COOC(n)H(m))(2), lack the phenolic hydroxyl group that is an essential structural component of the steroid A ring of 17 beta-estradiol. In order to examine whether dialkyl phthalates imitate the steroid structure, we have synthesized a series of 4-hydroxyl derivatives of dialkyl phthalates. The compounds were examined for their ability to displace [(3)H]17 beta-estradiol from the recombinant human estrogen receptor, which was expressed on Sf9 cells using the vaculovirus expression system. Dialkyl 4-hydroxyl phthalates were found to exhibit several-fold higher binding affinities compared to phthalates without the 4-hydroxyl group. From the analyses of receptor binding modes of dialkyl phthalates with and without the 4-hydroxyl group, it was deduced that the phthalic benzene ring mimics the steroid A ring. A biphasic binding curve observed for dicyclohexyl phthalate was also depicted by its 4-hydroxyl derivative, but it increased binding affinity only at the high affinity binding site. These data suggest that the phthalate benzene moiety recognizes the core of the estrogen receptor binding site and the hydrophobic interaction of the dialkyl moiety substantiates the binding characteristics of the phthalates. The present data indicate that even chemicals with slight structural analogy and weak receptor affinity can perturb the endocrine system when administered in high concentrations.
Asai
D
D
Laboratory of Structure-Function Biochemistry, Department of Chemistry, Faculty and Graduate School of Sciences, Kyushu University, Fukuoka 812-8581, Japan.
Tahara
Y
Y
Nakai
M
M
Yakabe
Y
Y
Takatsuki
M
M
Nose
T
T
Shinmyozu
T
T
Shimohigashi
Y
Y
D001665:Binding Sites; D001667:Binding, Competitive; D004958:Estradiol / Q000378:metabolism; D007700:Kinetics; D018716:Molecular Mimicry; D010795:Phthalic Acids / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D011960:Receptors, Estrogen / Q000378:metabolism*; D014316:Tritium; D015262:Xenobiotics / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
D010795:Phthalic Acids; D011960:Receptors, Estrogen; D015262:Xenobiotics; D014316:Tritium; D004958:Estradiol; C036042:dicyclohexyl phthalate