Effect of dose, time, and pretreatment on the biliary excretion and tissue distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat.
Previous studies of the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) pretreatment on the biliary excretion and hepatic disposition indicated that TCDD did not induce its own metabolic elimination. Pretreatment with TCDD did enhance its hepatic uptake. The present work was designed to further examine the effects of dose, time, and pretreatment on the tissue distribution and biliary elimination of [3H]TCDD. Adult male F-344 rats were administered 0 or 100 nmol [14C]TCDD or [3H]-TCDD/kg body weight po 3 days prior to bile duct cannulation and iv injection of 0 or 1 nmol [3H]TCDD or 1, 10, or 100 nmol [14C]TCDD/kg. Bile was collected for up to 8 hr while rats were maintained under pentobarbital anesthesia. Biliary TCDD and TCDD metabolites were quantified by liquid scintillation spectrometry. In naive animals which received no pretreatment, similar rates of excretion (% dose) were observed following iv administration of 1 nmol [3H]TCDD/kg or 10 or 100 nmol [14C]-TCDD/kg. Metabolic elimination of highly purified [3H]TCDD (> 99%) appeared to be linear with respect to time with approximately 0.8% of the dose being excreted in the bile over a 5- to 8-hr collection period 0 or 24 hr after iv dosing (1, 10, or 100 nmol/kg) and 72 hr after oral dosing (100 nmol/kg). In all groups, higher concentrations of TCDD were found in liver versus fat, and perirenal fat concentrations were elevated relative to epididymal fat concentrations, probably reflective of the enhanced blood perfusion of the former tissue. Pretreatment enhanced hepatic concentrations and decreased fat concentrations of the challenge dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Kedderis
L B
LB
Curriculum in Toxicology, University of North Carolina at Chapel Hill 27599.
Andersen
M E
ME
Birnbaum
L S
LS
D000818:Animals; D001646:Bile / Q000378:metabolism; D003314:Corn Oil / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000378:metabolism; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D012451:Safrole / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution
D065607:Cytochrome P-450 Enzyme Inhibitors; D000072317:Polychlorinated Dibenzodioxins; D003314:Corn Oil; D003577:Cytochrome P-450 Enzyme System; D019388:Cytochrome P-450 CYP1A2; D010089:Oxidoreductases, N-Demethylating; D012451:Safrole; C015959:isosafrole