Computer modelling of estrogenic transcriptional activation can account for different types of dose-response curves of estrogens

Abstract

Estrogenic activity of diphenylethanes and -ethenes was detd. 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 coeffs. nH from 0.3 to 2 corresponding to the mol. mechanism of estrogenic transcriptional activation. Binding of agonists (hormones, H) to estrogen receptors (ER) leads to receptor dimerization 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 affinity to short palindromic DNA sequences (estrogen responsive elements), can be proposed. Transcriptional activating functions of the DNA-bound ER are subsequently induced. The authors have derived an equil. model including these steps. Computer simulations of Hill plots based on the model have completely reproduced the range of obsd. nH values. Hill coeffs. are >1.5 if the homodimer H-ER-ER-H and <0.7 if the heterodimer H-Er-ER strongly predominates. If ER dimerization is disturbed (H-ER monomer predominant), nH is closer to 1. Hill coeffs. and pD2 values (neg. decadic logarithms of molar estrogen doses causing 50% of the maximal effects) are related to parameters of ER dimerization and the two steps of hormone-receptor dissocn. When a series of 1,2-bis(3'- or 4'-hydroxyphenyl)ethanes and -ethenes is studied, a rather simple dependence of nH and pD2 on the nature of alkyl groups sym. substituted at C-atoms 1 and 2 can be obsd. In terms of the model this implies that Et and a-branched higher alkyl substituents (nH.mchgt.1) appear to stabilize the homodimer, while Me and CF3 groups (nH.mchlt.1) could lead to a rapid dissocn. of the homodimer to the heterodimer. With longer n-alkyl and b-branched alkyl substitution (nH from 0.66 to 1.3), dimerization itself can be limited or the ligand-homodimer dissocn. is only moderately increased. Thus, a strong sterical constraint could exist with respect to the stabilization of the second ligand-receptor bond in the homodimer.