Effect of substituent size and dimensionality on potency of phenolic xenoestrogens evaluated with a recombinant yeast assay

Estrogenicity was assessed using the Saccharomyces cerevisiae-based Lac-Z r eporter assay and was reported as the logarithm of the inverse of the 50% m olar beta -galactosidase activity (log[EC50(-1)]). Previous studies indicat ed that the position, size, and shape of the nonphenolic moiety of xenoestr ogens affects potency. In an effort to quantify the relationship between th e size and shape of the nonphenolic moiety and estrogenic potency, a series of primarily hydrocarbon, para-substituted phenols were evaluated. There i s a general trend of increase in estrogenicity With increased substituent s ize. Attempts were made to correlate estrogenic activity with a variety of molecular parameters. These parameters included two-dimensional molecular c onnectivity and other topological indices, molecular orbital properties and other assorted steric properties, as well as hydrophobicity. Regression an alysis revealed that hydrophobicity, because of its colinearity with size, was moderately correlated with estrogenic activity (r(adj)(2) = 0.431). Amo ng the parameters describing the bulk and/or shape of the molecule, the sec ond-order path molecular connectivity for the substituent (2 chi (p(sub))) was the single best parameter correlated with estrogenicity. It modeled act ivity by the relationship log(EC50(-1)) = 0.925(2 chi (p(sub))) + 3.47; n = 28, s = 0.37, r(adj)(2) = 0.868, f = 179, p > 0.0001. In this model, the a ctive chemical domain is defined by the presence of the para-phenolic ring, while the potency is quantified by the values of the substituent connectiv ity index. A comparison of 3-, 5-, and 7-d estrogenicity and potency ratio, as compared with 17-beta -estradiol, showed some compounds that were not a ctive after the third day but that were active bn the fifth and seventh day s of exposure. Potency varied with length of exposure, but the potency rati o did not change. These results suggest that activity with this assay shoul d be reported after 5 d of exposure.