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...

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Veröffentlicht in:Chemical research in toxicology 1993-05, Vol.6 (3), p.328-334
Hauptverfasser: Kafafi, Sherif A, Afeefy, Hussein Y, Said, Hakim K, Kafafi, Abdel G
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creator Kafafi, Sherif A
Afeefy, Hussein Y
Said, Hakim K
Kafafi, Abdel G
description 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.
doi_str_mv 10.1021/tx00033a012
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Methods</topic><topic>Hydrocarbons - metabolism</topic><topic>Liver Neoplasms, Experimental - chemistry</topic><topic>Liver Neoplasms, Experimental - enzymology</topic><topic>Medical sciences</topic><topic>Oxidoreductases - biosynthesis</topic><topic>Rats</topic><topic>Receptors, Aryl Hydrocarbon</topic><topic>Receptors, Drug - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Toxicology</topic><topic>Tumor Cells, Cultured</topic><topic>Xenobiotics - toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kafafi, Sherif A</creatorcontrib><creatorcontrib>Afeefy, Hussein Y</creatorcontrib><creatorcontrib>Said, Hakim K</creatorcontrib><creatorcontrib>Kafafi, Abdel G</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Chemical research in toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kafafi, Sherif A</au><au>Afeefy, Hussein Y</au><au>Said, Hakim K</au><au>Kafafi, Abdel G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Chemical research in toxicology</jtitle><addtitle>Chem. Res. Toxicol</addtitle><date>1993-05-01</date><risdate>1993</risdate><volume>6</volume><issue>3</issue><spage>328</spage><epage>334</epage><pages>328-334</pages><issn>0893-228X</issn><eissn>1520-5010</eissn><abstract>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><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>8391339</pmid><doi>10.1021/tx00033a012</doi><tpages>7</tpages></addata></record>
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ispartof Chemical research in toxicology, 1993-05, Vol.6 (3), p.328-334
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subjects Animals
Aryl Hydrocarbon Hydroxylases - biosynthesis
Biological and medical sciences
Cytochrome P-450 CYP1A1
Cytochrome P-450 Enzyme System - biosynthesis
Disease Models, Animal
Enzyme Induction - drug effects
General aspects. Methods
Hydrocarbons - metabolism
Liver Neoplasms, Experimental - chemistry
Liver Neoplasms, Experimental - enzymology
Medical sciences
Oxidoreductases - biosynthesis
Rats
Receptors, Aryl Hydrocarbon
Receptors, Drug - metabolism
Structure-Activity Relationship
Toxicology
Tumor Cells, Cultured
Xenobiotics - toxicity
title 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
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