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.
Cynomolgus monkeys (Macaca fascicularis) have been used previously as a model to study effects on cytochrome P450 (CYP) regulation. Until now it has not been elucidated which CYP1A proteins are present in this primate species. The aim of this study was to characterize CYP1A in untreated hepatocytes of cynomolgus monkey using two specific CYP1A inhibitors (alpha-naphthoflavone and furafylline). The effect of different substituted polychlorinated biphenyls (PCBs) on CYP1A regulation was also studied in these hepatocytes. Small quantities of CYP1A2 have been identified in untreated hepatocytes. Northern blots showed the presence of a CYP1A mRNA in untreated hepatocytes, when hybridizations where performed with human CYP1A2 cDNA. Inhibitions with furafylline and alpha-naphthoflavone also suggested the presence of CYP1A2 properties. After induction with different PCBs, (probably) CYP1A1 mRNA and enzyme activity were induced in cynomolgus monkey hepatocytes. As expected, 2,3',4,4',5-PeCB (PCB no. 118), a mono-ortho substituted congener, was a potent CYP1A inducer but 2,2',3,4,4',5',5'-HpCB (PCB no. 180), a di-ortho and 2,2',3,4',5,5',6-HpCB (PCB no. 187), a tri-ortho substituted PCB, could induce CYP1A mRNA and enzyme activity in cynomolgus monkey hepatocytes as well.
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 physi‐cochemical parameters and different measures of the dose‐response curves. Relative effect potencies are predicted for the 154 tetra‐to 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.
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