Liver accumulation of 2,3,7,8-tetrachloro-[3H]dibenzofuran in mice: modulation by treatments with polychlorinated biphenyls.
The distribution of 2,3,7,8-tetrachloro-[3H]dibenzofuran ([3H]TCDF; 40 micrograms/kg) resembled that earlier reported for 2,3,7,8-tetrachlorodibenzo-p-dioxin, with a strong accumulation in the liver and a selective uptake in the nasal olfactory mucosa of adult and fetal mice. Pretreatments with a series of selected congeners of polychlorinated biphenyls (PCBs), i.e.. I (IUPAC)-77, I-105, I-118, I-126, I-153, I-156, I-169, and a commercial preparation, Aroclor 1254 (25-100 mg/kg body wt. i.p.), were found to modulate the hepatic uptake of [3H]TCDF (24 h post-3H-injection). At a short pretreatment time (4 h), non-ortho-chlorinated congeners decreased the uptake of [3H]TCDF equivalents in the liver (e.g., I-126 = 3,3',4,4',5-pentachlorobiphenyl: 34% of control), while several mono- and di-ortho PCB congeners and Aroclor 1254 increased the hepatic uptake of [3H]TCDF (e.g., I-156 = 2,3,3',4,4',5-hexachlorobiphenyl: 183% of control). At a longer pretreatment time (48 h), both a non-ortho (I-169 = 3,3',4,4',5,5'-hexachlorobiphenyl) and mono-ortho PCB congener(s) (e.g. I-156) markedly increased the hepatic 3H-uptake (190%), a probable effect of an induction of hepatic binding sites for TCDF. Ethoxyresorufin-O-deethylase activities, regarded to mirror the metabolic activity of cytochrome P-450 IA1 (CYP IA1), were strongly and time-dependently induced after I-169, but not after I-156, pretreatment (25 mg/kg). The initial liver concentrations of the two PCB congeners were similar and increased for I-169 but not for I-156 at later time points. In conclusion, the results show a selective uptake of [3H]TCDF in the mouse liver and nasal olfactory mucosa of both dam and fetus. The uptake of [3H]TCDF in the liver is influenced both by dose and pre-exposure with PCBs. The presence of a PCB-sensitive, but CYP IA1-independent, hepatic binding site for TCDF is suggested. Consequently, pharmacokinetic interactions with PCBs complicate the toxicity assessment of TCDF in complex mixtures.
Darnerud
P O
PO
Department of Toxicology, Uppsala University, Sweden.
Törnwall
U
U
Bergman
A
A
Brandt
I
I
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001345:Autoradiography; D001572:Benzofurans / Q000493:pharmacokinetics*; D020111:Chlorodiphenyl (54% Chlorine); D002849:Chromatography, Gas; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D004347:Drug Interactions; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010088:Oxidoreductases / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000493:pharmacokinetics / Q000494:pharmacology*; D011247:Pregnancy; D014018:Tissue Distribution
D001140:Aroclors; D001572:Benzofurans; D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; C014211:2,3,7,8-tetrachlorodibenzofuran