Comparative molecular field analysis of polyhalogenated dibenzo-p-dioxins, dibenzofurans, and biphenyls

Comparative molecular field analysis (CoMFA) was performed on polyhalogenated dibenzo-p-dioxins, dibenzofurans, and biphenyls for Ah (dioxin) receptor binding and associated enzyme inducing activities determined by others using in vitro assays. Since various members of all three classes of compounds have been shown to produce qualitatively similar toxicities, a separate CoMFA was performed on each class of compounds and combinations of the different classes for each bioactivity which included combining all three classes of molecules in one CoMFA study. For the Ah receptor binding, the CoMFA-derived QSARs for all three classes of compounds and combinations thereof showed strong crossvalidated correlations indicating that they are highly predictive. For enzyme induction, the CoMFA-derived QSARs were highly predictive for the dibenzofurans but were only partially successful for the dioxins. For the biphenyls, the results were clearly unpredictive. The overall results of these CoMFA studies which include both steric and electrostatic considerations are compared and contrasted to other SAR models that have met with some success in making qualitative predictions about the potential for receptor binding and associated toxicity in these classes of compounds. The CoMFA-derived QSAR for the dioxin series of molecules in most cases significantly overestimates the enzyme inducing ability of the ortho-substituted biphenyls. This weak inducing activity of the o-biphenyls is, however, consistent with their relatively low dioxin-like toxicity as measured in other biological systems. Fundamentally different mechanisms may be operating in the expression of dioxin-like toxic responses for the o-biphenyls, and their direct, dioxin-like toxic equivalency perhaps needs to be reconsidered in this light.