Absence of interactions on hepatic retention and 7-ethoxyresorufin-O-deethylation activity after co-administration of 1,2,3,7,8-pentachlorodibenzo-p-dioxin and 2,4,5,2',4',5'-hexachlorobiphenyl.
Interactions between 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PnCDD) and 2,4,5,2',4',5'-hexachlorobiphenyl (HxCB) on hepatic retention of PnCDD and on cytochrome P450 related enzyme activities were studied in male C57BL/6J mice. Animals received 8 nmol PnCDD/kg orally, alone or in combination with 1-416 mumol HxCB/kg. Co-administration of HxCB did not alter the hepatic retention of PnCDD or the 7-ethoxyresorufin-O-deethylation (EROD) activity induced by PnCDD as observed after 1 week. A small antagonistic effect on total cytochrome P450 content and 7-pentoxyresorufin-O-depentylation (PROD) activity was observed at a dose of 8 nmol PnCDD/kg and 1 mumol HxCB/kg. Furthermore, a significant induction of PROD activity by PnCDD was found. This was not expected, since PROD activity is considered to be a specific marker for CYP2b related enzyme activity and this type of cytochrome P450 is not induced by polychlorinated dibenzo-p-dioxins such as PnCDD. It is concluded that, under these short-term experimental conditions, no toxicokinetic basis was found to explain the antagonistic effects on hepatic cytochrome P450 related activities observed in the present study or in other studies.
De Jongh
J
J
Research Institute of Toxicology, University of Utrecht, The Netherlands.
Wondergem
F
F
Seinen
W
W
Van den Berg
M
M
D000818:Animals; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction; D007527:Isoenzymes / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010088:Oxidoreductases / Q000378:metabolism*; D011078:Polychlorinated Biphenyls / Q000493:pharmacokinetics / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D007527:Isoenzymes; D000072317:Polychlorinated Dibenzodioxins; C051452:1,2,3,7,8-pentachlorodibenzo-p-dioxin; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; C014024:2,4,5,2',4',5'-hexachlorobiphenyl