Structural essentials of xenoestrogen dialkyl phthalates to bind to the estrogen receptors

Xenoestrogen dialkyl phthalates. C6H4(COOCnHm)(2) lack the phenolic hydroxy l group that is an essential structural component of the steroid A ring of 17 beta -estradiol. In order to examine wh;ther dialkyl phthalates imitate the steroid structure, we have synthesized a series of 4-hydroxyl derivativ es of dialkyl phthalates. The compounds were examined for their ability to displace [H-3]17 beta -estradiol from the recombinant human estrogen recept or, which was expressed on Sf9 cells using the vaculovirus expression syste m. Dialkyl 4-hydroxyl phthalates were found to exhibit several-fold higher binding affinities compared to phthalates without the 4-hydroxyl group. Fro m the analyses of receptor binding modes of dialkyl phthalates with and wit hout the 4-hydroxyl group. it was deduced that the phthalic benzene ring mi mics 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 sugges t that the phthalate benzene moiety recognizes the core of the estrogen rec eptor binding site and the hydrophobic interaction of the dialkyl moiety su bstantiates the binding characteristics of the phthalates. The present data indicate that even chemicals with slight structural analogy and weak recep tor affinity can perturb the endocrine system when administered in high con centrations. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.