Substituted polychlorinated dibenzofuran receptor binding affinities and aryl hydrocarbon hydroxylase induction potencies--a QSAR analysis.
The rat hepatic cytosolic receptor binding affinities of 8-substituted 2,3-dichlorodibenzofurans and 8-substituted 2,3,4-trichlorodibenzofurans have been measured. The EC50-value for each compound was determined by dose-response competitive displacement of 2,3,7,8-[3H] tetrachlorodibenzo-p-dioxin (TCDD). Multiple parameter linear regression analysis of the data using several substituent parameters [lipophilicity (pi), hydrogen bonding (HB), electronegativity (sigma op), STERIMOL (delta B5)] demonstrated that for both sets of ligands, the binding affinities were dependent on substituent pi-values. The equations derived for the 8-substituted 2,3,4-trichlorodibenzofurans (a) and 8-substituted 2,3-dichlorodibenzofurans (b) were (Formula: see text) remarkably similar, moreover the relatively bulky t-butyl substituent was treated as an outlier for both calculations. The in vitro induction of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) in rat hepatoma H-4-II E cells by both sets of ligands demonstrated that there was not a rank order correlation between induction potencies and receptor binding affinities for these compounds. Analysis of the data for the 8-substituted 2,3-dichlorodibenofurans demonstrated that the monooxygenase enzyme induction was dependent on substituent lipophilicity and a STERIMOL (delta B5) factor which is related to (Formula: see text) substituent width. In contrast, the equation for the 8-substituted 2,3,4-trichlorodibenzofurans also included a substituent sigma op Hammett constant. The results indicate that although the binding affinities of the two sets of ligands are dependent only on substituent pi-values, their enzyme induction activities are both substituent and chlorine substitution pattern-dependent.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001572:Benzofurans; D001667:Binding, Competitive; D019363:Cytochrome P-450 CYP1A1; D003600:Cytosol / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism; D011108:Polymers; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001572:Benzofurans; D011108:Polymers; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; C016068:polychlorodibenzofuran; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1