Substituted polychlorinated dibenzofuran receptor binding affinites and aryl hydrocarbon hydroxylase induction potencies — A QSAR analysis

Abstract

The rat hepatic cytosolic receptor binding affinities of 8-substituted 2,3-dichlorodibenzofurans and 8-substituted 2,3,4-trichlorodibenzofurans have been measured. The EC 50-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 (π), hydrogen bonding (HB), electronegativity ( σ 0 p), STERIMOL ( ΔB 5)] demonstrated that for both sets of ligands, the binding affinities were dependent on substituent π-values. The equations derived for the 8-substituted 2,3,4-trichlorodibenzofurans (a) and 8-substituted 2,3-dichlorodibenzofurans (b) were log( 1 EC 50 )=1.09π+5.77 log( 1 EC 50 )=1.10π+5.19 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 ( ΔB 5) factor which is related to log( 1 EC 50 ) AHH=0.80π+0.87θB 5−0.35(θB 5) 2+4.63 log( 1 EC 50 ) AHH=0.76π−1.11θB 5+2.23ω °p+6.78 substituent width. In contrast, the equation for the 8-substituted 2,3,4-trichlorodibenzofurans also included a substituent σ 0 p Hammett constant. The results indicate that although the binding affinities of the two sets of ligands are dependent only on substituent π-values, their enzyme induction activities are both substituent and chlorine substitution pattern-dependent.