Effects of polychlorinated biphenyls on cytochrome P450 induction in the chick embryo hepatocyte culture.
The effects of pure synthetic polychlorinated biphenyl (PCB) congeners on the induction of cytochrome P450 and associated activities were examined in cultured chick embryo hepatocytes. Dose-response effects for the induction of total cytochrome P450 ethoxyresorufin-O-deethylase (EROD) activity, and benzphetamine demethylase (BPDM) activity were studied using 10 selected tetra- to hexachlorinated PCB congeners. These studies revealed that PCBs caused effects in the chick hepatocyte culture different from previously observed effects in rat liver. Based on their effects in chick hepatocytes, the PCBs could be categorized into two groups. The first group (consisting of 3,3',4,4'-PCB, 3,3',4,4',5-PCB, 3,3',4,4',5,5'-PCB, 2',3,3',4,5-PCB, 2,3,3',4,4',5'-PCB, and 2,3,4,4',5-PCB) induced total cytochrome P450 2.4- to 2.9-fold and EROD activity from 1-2 pmol/min/mg protein to 162-247. There was marked variation in potency, but all these congeners had a maximal inducing dose above which cytochrome P450 concentrations and EROD activities declined. BPDM activities were increased only slightly (1.2- to 1.6-fold) at the maximal cytochrome P450 inducing dose. The second group of congeners (consisting of 2,2',4,5,5'-PCB. 2,2',4,4',5,5'-PCB, and 2,2',3,4,4',6-PCB) induced total cytochrome P450 concentrations 4.0-fold and BPDM activities 2.2- to 2.6-fold with greatest activity occurring at the highest doses which could be added (10-50 microM). However, EROD activities were also increased by these congeners to 60-112 pmol/min/mg protein with declining activities seen at the highest PCB doses (i.e., resembling EROD induction patterns of the first group). The EROD induction patterns with these latter PCB congeners are noteworthy since these PCBs do not induce EROD activity in the rat. For both groups of PCB congeners, EROD induction was associated with increased accumulation of uroporphyrin in cultures exposed to exogenous 5-aminolevulinate. Studies investigating the reason for the depression of cytochrome P450 concentrations and/or EROD activities by high doses of the PCBs revealed that with the first group there was slightly decreased total protein synthesis, decreased total cell heme concentrations, and decreased accumulation of radiolabeled heme synthesized from 5-[14C]aminolevulinate. These changes might represent nonspecific toxic effects of the first group of PCBs. However, since these changes were not seen with the second group of PCBs, it is unlikely that either inhibition of heme synthesis or toxicity cause the depression of EROD activity with high PCB doses.
Rodman
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Graduate Center for Toxicology, University of Kentucky, Lexington 40506-0054.
Shedlofsky
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Swim
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Robertson
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D000502:Allylisopropylacetamide / Q000494:pharmacology / Q000031:analogs & derivatives; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D006581:Hexachlorobenzene / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008748:Methylcholanthrene / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000502:Allylisopropylacetamide; D006581:Hexachlorobenzene; D008748:Methylcholanthrene; C009072:propylisopropylacetamide; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010634:Phenobarbital