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 EC50 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 EC50 values for receptor and the -log EC50 values for AHH (or EROD) induction; moreover, a comparable linear relationship was observed between the -log EC50 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, OCH3, NO2, COCH3, F, CF3, CH3, C2H5, i-C3H7, n-C4H9 and t-C4H9). Not unexpectedly, there was a linear relationship between the -log EC50 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/EC50) = 1.53 sigma + 1.47 pi + 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 sigma = electronegativity, pi = hydrophobicity (log P) and HB = hydrogen bonding capacity for the substituent groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Preferential induction of the rat hepatic P450 I proteins by the food carcinogen 2‐amino‐3‐methyl‐imidazo[4,5‐f]quinoline

“…Tween 20. Non-specific binding was corrected by using the appropriate preimmune sera [23,41,42]. Planarity is a prerequisite but not a condition for P450 I induction.…”

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…AhR binds to xenobiotic responsive elements and mediates the induction of cytochrome P450 1A1 by TCDD (Whitlock et al, 1989). In addition to TRANSPORTER FUNCTION AND REGULATION TCDD, other AhR ligands include polychlorinated biphenyls, 3-methylcholanthrene, and ␤-naphthoflavone (Safe et al, 1985;Köhle and Bock, 2006). AhR ligands elevate hepatic expression of Mrps as well as Oatp2b1 and -3a1 mRNA in mice and decrease Oatp1a4 mRNA in rats (Figs.…”

Molecular Mechanism of Inhibition of Estrogen-Induced Cathepsin D Gene Expression by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) in MCF-7 Cells

“…Although the endogenous ligand(s) for this receptor has not been identified, several different classes of compounds reversibly bind the Ah receptor, and these include the polynuclear and polyhalogenated aromatic hydrocarbons (42,54,57,59,65,67). 3-Methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are prototypical aromatic hydrocarbons which exhibit high-affinity binding (K d Յ 1 nM) for the Ah receptor (44, 58) and have been utilized for characterizing Ah receptor-mediated responses.…”