Binding of polychlorinated biphenyls to the aryl hydrocarbon receptor.

A new thermodynamic model for calculating the dissociation constants of complexes formed between the aryl hydrocarbon receptor (AhR) and polychlorinated biphenyls (PCBs) is reported. The free energies of binding of PCBs to AhR are controlled by their lipophilicities, electron affinities, and entropies. The corresponding physicochemical properties of polychlorinated dibenzo-p-dioxins and dibenzofurans also control their interactions with AhR. We present evidence supporting the hypothesis that the majority of PCBs are likely to interact with AhR in their nonplanar conformations. In addition, we demonstrate that the affinities of PCBs for AhR relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin correlate with corresponding toxic equivalency factors in animals. The reported methodology is likely to be applicable to other polyhalogenated and mixed polyhalogenated bi- and terphenyls and related xenobiotics; thus, it could minimize the number of in vivo studies in laboratory animals and facilitate the identification of potentially hazardous aromatic xenobiotics.

Affinities for the aryl hydrocarbon receptor, potencies as aryl hydrocarbon hydroxylase inducers and relative toxicities of polychlorinated biphenyls. A congener specific approach.

Polychlorinated biphenyls (PCBs) are nonplanar aromatic xenobiotics that are not structurally related to polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), yet, some PCBs are potent ligands for the aryl hydrocarbon receptor (AhR), active inducers of aryl hydrocarbon hydroxylase (AHH) and 7-ethoxyresorufin O-deethylase (EROD), and elicit toxicological responses in animals similar to PCDDs and PCDFs. We report new methodologies for quantifying the affinities of PCBs for AhR and corresponding potencies as AHH and EROD inducers. The models show that lipophilicities, electron affinities, entropies and electronic energy gaps of PCBs are key physicochemical properties controlling their AhR, AHH and EROD activities. Using 3,3',4,4'-tetrachlorobiphenyl (TCB) as the reference compound, it is shown that PCBs having higher electron affinities, lower lipophilicities and entropies than TCB are potent ligands for rat hepatic AhR. In addition, the congeners having higher binding affinities to AhR and smaller energy gaps than TCB are potent AHH and EROD inducers in rat hepatoma cells in culture. The reported models qualitatively explain and quantify AhR, AHH and EROD activities of all 209-PCBs and related xenobiotics, e.g. PCDDs and PCDFs. Furthermore, we demonstrated that AhR and AHH activities of PCBs relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin correlate with corresponding in vivo relative toxicities in animals as well as assigned toxic equivalency factors. The reported methodologies are likely to be useful for identifying potentially toxic aromatic xenobiotics in mammals, and minimizing the need for animal testing.

Relationship between aryl hydrocarbon receptor binding, induction of aryl hydrocarbon hydroxylase and 7-ethoxyresorufin O-deethylase enzymes, and toxic activities of aromatic xenobiotics in animals. A new model.

A new mathematical model relating the affinities of aromatic xenobiotics for the aryl hydrocarbon receptor (AhR) to their potencies as aryl hydrocarbon hydroxylase (AHH) and 7-ethoxyresorufin O-deethylase inducers and toxic activities in animals is reported. Taking polychlorinated dibenzo-p-dioxins (PCDDs) as examples, the AHH activity of a PCDD relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is shown to be analytically related to corresponding relative affinities for AhR, and electronic energy gaps of PCDD and TCDD. (The electronic energy gap of a chemical is the difference between its ionization potential and electron affinity.) The reported model is capable of qualitatively explaining and quantitatively estimating potencies of PCDDs and related xenobiotics as AHH inducers in rat hepatoma H-4-II E cells in culture. Therefore, a PCDD is expected to be a potent AHH inducer if its affinity for AhR is high and has a smaller energy gap than TCDD. In addition, it is shown that the derived equations for AHH induction by PCDDs apply equally well to 7-ethoxyresorufin O-deethylase (EROD) activities; that is, there is a 1:1 correspondence between AHH and EROD activities for PCDDs, in agreement with experimental findings. Furthermore, in harmony with experimental observations, AHH (and EROD) activities of PCDDs relative to TCDD parallel the corresponding toxic equivalency factors and AhR mediated in vivo toxicities of these xenobiotics in animals, such as thymic atrophy, body weight loss, and acute lethalities. Moreover, the developed methodology for AHH and EROD induction by PCDDs is shown to apply to polychlorinated dibenzofurans, thus, eliminating cross-class comparison problem of traditional structure-activity studies.(ABSTRACT TRUNCATED AT 250 WORDS)

A new structure-activity model for Ah receptor binding. Polychlorinated dibenzo-p-dioxins and dibenzofurans.

A new structure-affinity model for the aromatic hydrocarbon (Ah) receptor is reported. The proposed mathematical model completely eliminates multiple regression analysis in its formulation and overcomes the cross-class comparison inherent to classical quantitative structure-activity relationships. Taking the polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) as model xenobiotics, the binding affinity of a PCDD relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is shown to be analytically related to the electron affinities, entropies, and lipophilicities of PCDD and TCDD. From the calculated dissociation constants of PCDD-Ah receptor complexes, the corresponding equilibrium constants of PCDF-Ah complexes could be computed, in agreement with the experimental observation that the trend in the binding affinities of PCDDs and PCDFs to the Ah receptor are similar. The reported model is capable of quantitatively explaining the quantitatively estimating the in vitro binding affinities of PCDDs, PCDFs, and related xenobiotics to the Ah receptor. Therefore, a halogenated aromatic compound is expected to have a higher affinity for the cytosolic protein than TCDD if it is less lipophilic and has a higher electron affinity and lower entropy. Furthermore, the affinities of structurally related polychlorinated aromatic xenobiotics for the Ah receptor could be computed from their entropies and electron affinities.

The electronic and thermodynamic aspects of Ah receptor binding. A new structure-activity model: I. The polychlorinated dibenzo-p-dioxins.

A new quantitative structure-activity model for the aromatic hydrocarbon (Ah) receptor, which completely eliminates multiple regression analysis in its formulation, is reported. Taking the polychlorinated dibenzo-p-dioxins (PCDDs) as model xenobiotics, the binding affinity of a PCDD relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was found to be analytically related to the electron affinities, entropies and lipophilicities of PCDD and TCDD. The reported mathematical model is capable of qualitatively explaining and quantitatively estimating the in vitro binding affinities of PCDDs and related xenobiotics to the Ah receptor. Accordingly, a halogenated aromatic compound is expected to have a high affinity for the cytosolic protein compared to TCDD if it is less lipophilic, has a higher electron affinity and lower entropy than TCDD. In addition, the LD50s of PCDDs in selected mammalian species are shown to have similar sigmoidal dependence on their lipophilicities, electron affinities and entropies, in agreement with the hypothesis that the toxicities of PCDDs and related xenobiotics are mediated through binding to the Ah receptor and that the trend in the LD50s and other toxic responses of PCDDs in animals are similar.