Effects of structure on binding to the 2,3,7,8-TCDD receptor protein and AHH induction--halogenated biphenyls.

Abstract

The quantitative structure-activity relationships (QSARs) for polychlorinated biphenyl (PCB) congeners have been determined by comparing the ECQ, values for three in vitro test systems, namely, aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) induction in rat hepatoma H-4-II-E cells and competitive binding avidities to the rat cytosolic receptor protein (using 2,3,7,8-tetrachlorodibenzo-p-dioxin as a radioligand). For several PCB congeners that are in vivo inducers of rat hepatic microsomal AHH, there was a linear correlation between the -log EC.4 values for receptor and&the -log ECso values for AHH (or EROD) induction; moreover, a comparable linear relationship was observed between the -log EC.4 values for AHH and EROD induction. Previous in vivo studies have shown that the most active PCB congeners 3,3',4,4'-tetra-, 3,4,4',5-tetra-, 3,3',4,4',5-penta-, and 3,3',4,4',5,5'-hexachlorobiphenyl, cause many of the biologic and toxic effects reported for the highly toxic halogenated aryl hydrocarbon, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Moreover, the monoortho-substituted homologs of the four coplanar PCBs also elicit comparable in vivo biologic and toxic responses. It was evident from the QSARs for PCBs that there was an excellent correspondence between the in vivo and in vitro potencies of the individual PCB congeners.The effects of substituents on both receptor binding and AHH/EROD induction was determined for a series of 4'-substituted (X)-2,3,4,5-tetrachlorobiphenyls (where X = H, Cl, Br, I, OH, OCH,, NO2, COCH3, F, CF3, CH3, C2HA, i-C3H7, n-C4H, and t-C4H,). Not unexpectedly, there was a linear relationship between the -log ECso values for AHH and EROD induction, and these results confirm that both enzymatic oxidations are catalyzed by the same cytochrome P-450 isozyme(s). The effects of substituent structure on receptor binding for 12 substituents was subjected to multiple regression analysis which correlates the relative binding affinities of the compounds with the physical chemical characteristics of the substituents. The analysis gave the following equation: log (1/EC,0) = 1.53a + 1.47Th + 1.09 HB + 4.08 for n = 12, s = 0.18, r = 0.978; where n is the number of substituents, s is the standard deviation, r is the correlation coefficient, and af = electronegativity, -T = hydrophobicity (log P) and HB = hydrogen bonding capacity for the substituent groups. The data suggest that the latter three parameters facilitate the interaction between.the ligand and the cytosolic receptor protein. The effects of two lateral substituents on ligandreceptor interactions are not readily explained by the above relationship and may depend on other substituent physical chemical parameters.

Use of an mfo‐directed toxicity identification evaluation to isolate and characterize bioactive impurities from a lampricide formulation

“…Molecules with nitro-substitution at the 8-position also showed a high affinity for the receptor (binding pEC50 7.45 vs. 8.00 for [ 3 H]-TCDD). Similar binding affinities were also noted in a more recent study using the human placental cytosolic Ah receptor [32] and with PCBs containing these substituents [33]. Substitution in the lateral 2, 3, 7, or 8 positions is generally required for highest Ah receptor affinity.…”

The Role of Ligand Flexibility in Predicting Biological Activity: Structure–activity Relationships for Aryl Hydrocarbon, Estrogen, and Androgen Receptor Binding Affinity

“…Our first evaluation of the dynamic QSAR method in terms of receptor-ligand interactions focused on binding of halogenated aromatic compounds to the AhR [23]. The relative affinity for the AhR of individual congeners of polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), and polychlorinated dibenzo-p-dioxins (PCDDs) is strongly correlated with the induction of hepatic cytochrome P4501A1mediated activities and a variety of toxic responses, including thymic atrophy, body weight loss, immunotoxicity, and acute mortality [24][25][26][27][28][29][30][31]. Hence, accurate prediction of the affinity of chemicals for the AhR is key to assessing potential toxicity.…”

Comparative Developmental Toxicity of Planar Polychlorinated Biphenyl Congeners in Chickens, American Kestrels, and Common Terns

“…The most acutely toxic PCB congeners, including 3,3Ј,4,4Ј,5-pentaCB (PCB 126), can assume coplanar conformations generally similar to that of 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD). Common toxic responses most widely documented in mammals include thymic atrophy, a wasting syndrome, immunotoxic effects, reproductive impairments, porphyria and related liver damage, and induction of specific isozymes of the cytochrome P450 system [6][7][8][9][10]. Gilbertson et al [11] and others [4,12,13] have documented and reviewed the history of PCB-related reproductive problems in Great Lakes fish-eating birds and their classification as GLEMEDS, Great Lakes Embryo Mortality, Edema, and Deformities Syndrome.…”