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,...

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Bibliographic Details
Published in:Carcinogenesis (New York) 1992-09, Vol.13 (9), p.1599-1605
Main Authors: Kafafi, Sherif A., Said, Hakim K., Mahmoud, Mahmoud I., Afeefy, Hussein Y.
Format: Article
Language:English
Subjects:
Biological and medical sciences
Carcinogenesis, carcinogens and anticarcinogens
Chemical agents
Dioxins - metabolism
Electrons
Medical sciences
Models, Chemical
Polychlorinated Dibenzodioxins - metabolism
Receptors, Aryl Hydrocarbon
Receptors, Drug - metabolism
Structure-Activity Relationship
Thermodynamics
Tumors
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Summary: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 toxkities 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.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/13.9.1599