Potency of mixtures of polychlorinated biphenyls as inducers of dioxin receptor-regulated CYP1A activity in rat hepatocytes and H4IIE cells.
Among the polychlorinated biphenyls (PCBs), a family of widespread environmental pollutants, the most toxic non-ortho-substituted coplanar (non-ortho coplanar) congeners are thought to act as strong dioxin (aryl hydrocarbon) receptor agonists leading to adverse effects, such as body weight loss, immunosuppression, thymic atrophy, hepatotoxicity, tumor promotion, and disturbances of steroid hormone action. Since PCBs are present in environmental and tissue samples as complex mixtures, we investigated the possible interaction of non-ortho coplanar congeners with other major PCBs, which are less active or inactive as dioxin receptor agonists. As a parameter for dioxin receptor activation, induction of CYP1A-catalyzed 7-ethoxyresorufin O-deethylase (EROD) was determined in rat hepatocytes in primary culture and in the rat hepatoma cell line H4IIE. In rat hepatocytes, individual EC50-values and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalency factors (TEFs) for the non-ortho and mono-ortho coplanar PCBs 126, 169, 105, 118 and 156, were in good agreement with published data from in vivo experiments, while in H4IIE cells coincidence was lower. However, in both cell systems TEFs for PCB 77 were significantly higher than reported from experiments in rats. In an approximately equipotent mixture the six potent PCB congeners showed perfect additive behaviour in both cell systems. In contrast, addition of a tenfold surplus of abundant mono- and di-ortho PCBs (28, 52, 101, 138, 153 and 180) led to an almost threefold higher TEF than predicted. This finding suggests a moderate synergistic enhancement of the inducing potency of potent PCBs by less potent congeners, present in abundance in environmental and tissue samples.
Schmitz
H J
HJ
Institute of Toxicology, University of Tübingen, Germany.
Hagenmaier
A
A
Hagenmaier
H P
HP
Bock
K W
KW
Schrenk
D
D
D000818:Animals; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D010088:Oxidoreductases / Q000096:biosynthesis*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D018336:Receptors, Aryl Hydrocarbon; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1