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Effect of substituent size and dimensionality on potency of phenolic xenoestrogens evaluated with a recombinant yeast assay
Author(s) -
Schultz T. Wayne,
Sinks Glendon D.,
Cronin Mark T.D.
Publication year - 2000
Publication title -
environmental toxicology and chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.1
H-Index - 171
eISSN - 1552-8618
pISSN - 0730-7268
DOI - 10.1002/etc.5620191104
Subject(s) - substituent , potency , chemistry , stereochemistry , quantitative structure–activity relationship , moiety , lipophilicity , topological index , steric effects , biochemistry , computational chemistry , in vitro
Estrogenicity was assessed using the Saccharomyces cerevisiae ‐based Lac ‐ Z reporter assay and was reported as the logarithm of the inverse of the 50% molar β‐galactosidase activity (log[EC50 −1 ]). Previous studies indicated that the position, size, and shape of the nonphenolic moiety of xenoestrogens affects potency. In an effort to quantify the relationship between the size and shape of the nonphenolic moiety and estrogenic potency, a series of primarily hydrocarbon, para ‐substituted phenols were evaluated. There is a general trend of increase in estrogenicity with increased substituent size. Attempts were made to correlate estrogenic activity with a variety of molecular parameters. These parameters included two‐dimensional molecular connectivity and other topological indices, molecular orbital properties and other assorted steric properties, as well as hydrophobicity. Regression analysis revealed that hydrophobicity, because of its colinearity with size, was moderately correlated with estrogenic activity ( r 2 adj = 0.431). Among the parameters describing the bulk and/or shape of the molecule, the second‐order path molecular connectivity for the substituent ( 2 χ p ( sub ) was the single best parameter correlated with estrogenicity. It modeled activity by the relationship log(EC50 −1 ) = 0.925( 2 χ p ( sub ) + 3.47; n = 28, s = 0.37, r 2 adj = 0.868, f = 179, p > 0.0001. In this model, the active chemical domain is defined by the presence of the para ‐phenolic ring, while the potency is quantified by the values of the substituent connectivity index. A comparison of 3‐, 5‐, and 7‐d estrogenicity and potency ratio, as compared with 17‐β‐estradiol, showed some compounds that were not active after the third day but that were active on the fifth and seventh days of exposure. Potency varied with length of exposure, but the potency ratio did not change. These results suggest that activity with this assay should be reported after 5 d of exposure.