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)
Department of Environmental Health Sciences, Johns Hopkins University, School of Hygiene and Public Health, Baltimore, Maryland 21205.
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D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000187:drug effects; D006838:Hydrocarbons / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000737:chemistry / Q000201:enzymology; D010088:Oxidoreductases / Q000096:biosynthesis*; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D015262:Xenobiotics / Q000633:toxicity*
D006838:Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1