The competitive receptor binding affinities of thirteen 2-substituted 3,7,8-trichlorodibenzo-p-dioxins to hepatic cytosol from rat, mouse, guinea pig, and hamster were determined with [3H]-2,3,7,8-tetracliloro-dlbenzo-p-dioxin as the radioligand. Multiple parameter linear regression analysis of the binding data from the four species gave the following equations: [formula omitted] where [formula omitted] and [formula omitted] are physicochemical parameters for substituent lipophilicity, steric effect, hydrogen bonding capacity, electronegativity, and van der Waals volume (relative to H), respectively. These equations demonstrate that there are important species differences in the receptor protein binding site interactions with the substituted analogues. These data, coupled with the known species differences in the molecular properties of the receptor proteins, are evidence for a heterologous nature of the receptor between mammalian species. Multiple parameter linear regression analysis of the relative aryl hydrocarbon hydroxylase (AHH) induction potencies of these analogues in rat hepatoma H-4-II E-cells in culture gave the following equation. The correlation [formula omitted] between receptor binding and AHH induction was dependent on a steric parameter (Î”B5, STERIMOL) and the results suggest that an additional substituent-dependent process (e.g., an activation step) may be required after initial ligand-receptor binding for the ultimate expression of the receptor-mediated response (i.e., AHH induction). Â© 1987, American Association for Cancer Research. All rights reserved.