Multivariate Modeling of Polychlorinated Biphenyl–induced Cyp1a Activity in Hepatocytes From Three Different Species: Ranking Scales and Species Differences

Abstract

Abstract-Cytochrome P4501A-induced activity of 20 selected polychlorinated biphenyls (PCBs) was evaluated by measuring ethoxyresorufin-O-deethylase and methoxyresorufin-O-demethylase activities induced in the hepatocytes of cynomolgus monkeys, male castrated pigs, and chicken embryos. Quantitative structure-activity relationships have been established, including 52 physicochemical parameters and different measures of the dose-response curves. Relative effect potencies are predicted for the 154 tetrato hepta-PCBs and reported for the most potent congeners according to both EC50 and maximal response values. Important physicochemical parameters of the PCBs as related to the modeled activity are parts of their ultraviolet absorption spectra, the Henry's law constant, the ionization potential, and the octanol-water partition coefficient. Interspecies differences were found in terms of varied sensitivity to different structural subgroups of the compounds. The chicken hepatocyte assay showed the most specific structure-activity relationship, with high activity for the non-ortho PCBs, whereas the pig hepatocytes responded even for some di-to tetra-ortho PCBs. An interspecies response, the principal induction potency, is presented for the 41 most potent PCBs. These responses showed strong correlation with the toxic equivalency factors and are likely to be useful in risk assessment of the compounds.

Structure−Activity Relationships for the Toxicity of Polychlorinated Dibenzofurans: Approach through Density Functional Theory-Based Descriptors

“…Nonexistence of a linear correlation between the BA and the AHH and EROD induction potencies of PCDFs is reflected in the above models showing that the results obtained in these models (eqs [19][20][21][22][23][24] were not as good as those obtained in binding affinity models (eqs [16][17][18]. Still, these models explain about 63-69% of variation in induction potencies.…”

“…It is clear from the derived regressions that even though the chemical softness has emerged as the best descriptor among the three DFT descriptors in the linear regressions (7-15) describing biological activities of PCDFs, the other two descriptors, electronegativity and electrophilicity index, provide better correlations (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) in combination with log P and/or L max values. Further studies on other molecules are necessary to make a concrete explanation for this fact.…”

“…These descriptors were considered in a few studies to study the toxicity of molecules: Schuurmann (21) has used η and as descriptors along with many other descriptors in his QSAR analysis for the toxicity of 10 phosphorothionates; Kobayashi et al (22) showed the correlation between the hardness values of the selected dioxins with their potency of biological activities. Both η and were used along with the number of parameters in multivariate physicochemical characterization and QSAR modeling of PCBs, polybrominated diphenyl ethers, and hydroxylated PCBs (23)(24)(25)(26). In all of the above studies, semiempirically calculated HOMO (highest occupied molecular orbital) and LUMO energies were used to obtain the η and values.…”

Integrated Biomonitoring of Dioxin-like Compounds for Waste Management and Environment.

“…In vivo EROD assay has been conducted as a biomarker of exposure to PHAHs. Liver microsome containing CYP1A1 is extracted from animals such as rat, mouse, fish and wild bird, and their EROD activity can be measured [2][3][4][5][6][7][8] .…”

Induction of cytochrome P4501A in African brown house snake (Lamprophis fuliginosus) primary hepatocytes

“…A sensitive response to the binding of HAHs to the aryl hydrocarbon (Ah) receptor is the induction of ethoxyresorufin‐ O ‐deethylase (EROD). The activity of EROD is directly associated with the induction of hepatic cy‐tochrome P4501A and is commonly used as a marker to test for effects of HAHs in many vertebrate species [2,3,10]. Whereas both the presence and effects of HAHs have been studied intensely in mammals, birds, fish, and turtles [2,3,8,11–14], little information is available on other reptilian species [15,16].…”