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

Abstract

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 1000µmol 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-ethoxyres-orufin-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 CYPlA2-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.