Induction of cytochrome P450 isoenzymes after toxicokinetic interactions between 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,2',4,4',5,5'-hexachlorobiphenyl in the liver of the mouse.
One group of male C57BL/6J mice received a single oral dose of 1 nmol 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg. Six other groups received single oral doses of 100, 300, or 1000 mumol 2,2',4,4',5,5'-hexachlorobiphenyl (HxCB)/kg, alone or in combination with 1 nmol/kg TCDD. Liver deposition of both compounds was studied at Day 3 after dosage. Hepatic CYP1A1 and CYP1A2 protein levels and related 7-ethoxyresorufin-O-deethylation (EROD) and acetanilide 4-hydroxylation (ACOH) activities were also studied. A significant increase in the hepatic deposition of TCDD was observed in all three mixed dose groups but TCDD did not influence hepatic HxCB deposition. TCDD did increase both CYP1A1 and CYP1A2 protein levels. In the HxCB-treated groups, CYP1A2 levels were also increased in a dose-dependent way but CYP1A1 levels were not increased. CYP1A2 activities (ACOH), but not protein levels, in the TCDD groups cotreated with HxCB were higher than those in the group treated with TCDD alone. CYP1A1-dependent EROD activity and CYP1A2-dependent ACOH activity were induced in all treated dose groups. It is concluded that the present results do not confirm a direct role of CYP1A2 induction in the increase of hepatic TCDD levels by HxCB cotreatment in the mixed HxCB/TCDD dose groups. However, in this aspect, the discrepancy between CYP1A2 activities and protein levels remains to be explained.
De Jongh
J
J
Research Institute of Toxicology, Utrecht University, The Netherlands.
DeVito
M
M
Nieboer
R
R
Birnbaum
L
L
Van den Berg
M
M
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004347:Drug Interactions; D004790:Enzyme Induction; D015151:Immunoblotting; D007527:Isoenzymes / Q000096:biosynthesis; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000096:biosynthesis; D011078:Polychlorinated Biphenyls / Q000493:pharmacokinetics* / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000493:pharmacokinetics* / Q000633:toxicity*
D007527:Isoenzymes; D000072317:Polychlorinated Dibenzodioxins; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; C023738:acetanilide hydroxylase; C014024:2,4,5,2',4',5'-hexachlorobiphenyl