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Estrogenicity of benzophenones evaluated with a recombinant yeast assay: Comparison of experimental and rules‐based predicted activity
Author(s) -
Schultz T. Wayne,
Seward Julie R.,
Sinks Glendon 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.5620190208
Subject(s) - chemistry , moiety , ec50 , benzophenone , substituent , stereochemistry , acute toxicity , potency , yeast , toxicity , derivative (finance) , biological activity , in vitro , biochemistry , organic chemistry , economics , financial economics
In a previous study, structure‐based rules were formulated to predict estrogenicity of phenolic molecules. The determination of estrogenic activity (EC50) and acute toxicity (LC50) of benzophenones was undertaken, and experimental and predicted estrogenic potency values were compared. The Saccharomyces cerevisiae ‐based lac ‐Z reporter assay was used to generate experimental data. Estrogenicity was measured colormetrically as β‐galactosidase activity. On the basis of the series of rules, β‐galac‐tosidase activity was predicted correctly for 14 of the 18 benzophenones tested. As predicted, benzophenone, as well as derivatives with a methyl‐, chloro‐, or nitro‐substituent, exhibited no β‐galactosidase activity. As anticipated, 4‐hydroxybenzophenone exhibited weak β‐galactosidase activity (EC50 value of e‐06 M). The 3‐hydroxybenzophenone exhibited almost the same activity as the 4‐hydroxy derivative, whereas the 2‐hydroxy derivative was nonactive. It was observed while replacing the para ‐hydroxyl group with an amino moiety decreased β‐galactosidase activity by a half order of magnitude, replacement of the para ‐hydroxy moiety with a methoxy group negated activity. The nonsymmetrical trihydroxylated benzophenone exhibited activity near to the monohydrox‐yl derivative. Near symmetrical tri‐ and symmetrical tetrahydroxylated benzophenones were determined to have greater estrogenic activity (EC50 values of e‐07 M) than nonsymmetrical molecules. A comparison of estrogenicity (EC50) with acute toxicity (LC50) reveals a less than a 10‐fold difference in activities for weaker estrogenic compounds. However, the more hydrophilic, stronger estrogenic compounds typically exhibit a difference of two to three orders of magnitude between EC50 and LC50 values.