COMPUTER MODELING OF ESTROGENIC TRANSCRIPTIONAL ACTIVATION CAN ACCOUNT FOR DIFFERENT TYPES OF DOSE-RESPONSE CURVES OF ESTROGENS

Estrogenic activity of diphenylethanes and -ethenes was determined by uterine growth in immature mice and analyzed by weighed regression of logit-transformed effect on log dose values. This resulted in a range of Hill coefficients n(H) from 0.3 to 2 corresponding to the molecular mechanism of estrogenic transcriptional activation. Binding of agonis ts (hormones, H) to estrogen receptors (ER) leads to receptor dimeriza tion depending on the structure of the ligand. Three hormone-receptor complexes, H-ER, H-ER-ER, and H-ER-ER-H, which bind with different aff inity to short palindromic DNA sequences (estrogen responsive elements ), can be proposed. Transcriptional activating functions of the DNA-bo und ER are subsequently induced. We have derived an equilibrium model including these steps. Computer simulations of Hill plots based on the model have completely reproduced the range of observed n(H) values. H ill coefficients are >1.5 if the homodimer H-ER-ER-H and <0.7 if the h eterodimer H-ER-ER strongly predominates. If ER dimerization is distur bed (H-ER monomer predominant), n(H) is closer to 1. Hill coefficients and pD2 values (negative decadic logarithms of molar estrogen doses c ausing 50% of the maximal effects) are related to parameters of ER dim erization and the two steps of hormone-receptor dissociation. When a s eries of 1,2-bis(3'-or 4'-hydroxyphenyl)ethanes and -ethenes is studie d, a rather simple dependence of n(H) and pD2 on the nature of alkyl g roups symmetrically substituted at C-atoms 1 and 2 can be observed. In terms of the model this implies that ethyl and alpha-branched higher alkyl substituents (n(H) >> 1) appear to stabilize the homodimer, whil e methyl and CF3 groups (n(H) << 1) could lead to a rapid dissociation of the homodimer to the heterodimer. With longer n-alkyl and beta-bra nched alkyl substitution (n(H) from 0.66 to 1.3), dimerization itself can be limited or the ligand-homodimer dissociation is only moderately increased. Thus, a strong sterical constraint could exist with respec t to the stabilization of the second ligand-receptor bond in the homod imer.