Estrogenicity of benzophenones evaluated with a recombinant yeast assay: Comparison of experimental and rules-based predicted activity

In a previous study, structure-based rules were formulated to predict estro genicity of phenolic molecules. The determination of estrogenic activity (E C50) and acute toxicity (LC50) of benzophenones was undertaken, and experim ental and predicted estrogenic potency values were compared. The Saccharomy ces cerevisiae-based lac-Z reporter assay was used to generate experimental data. Estrogenicity was measured colormetrically as beta-galactosidase act ivity. On the basis of the series of rules, beta-galactosidase activity was predicted correctly for 14 of the Is benzophenones tested. As predicted, b enzophenone, as well as derivatives with a methyl-, chloro-, or nitro-subst ituent, exhibited no beta-galactosidase activity. As anticipated, 4-hydroxy benzophenone exhibited weak beta-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 decre ased beta-galactosidase activity by a half order of magnitude, replacement of the para-hydroxy moiety with a methoxy group negated activity. The nonsy mmetrical trihydroxylated benzophenone exhibited activity near to the monoh ydroxyl derivative. Near symmetrical tri- and symmetrical tetrahydroxylated benzophenones were determined to have greater estrogenic activity (EC50 va lues of e-07 M) than nonsymmetrical molecules. A comparison of estrogenicit y (EC50) with acute toxicity (LC50) reveals a less than a 10-fold differenc e in activities for weaker estrogenic compounds. However, the more hydrophi lic, stronger estrogenic compounds typically exhibit a difference of two to three orders of magnitude between EC50 and LC50 values.