Effect of Dose, Time, and Pretreatment on the Biliary Excretion and Tissue Distribution of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in the Rat
| Autor: | Lorrene Buckley Kedderis, Melvin E. Andersen, Linda S. Birnbaum |
|---|---|
| Rok vydání: | 1993 |
| Předmět: |
Male
endocrine system medicine.medical_specialty Polychlorinated Dibenzodioxins Time Factors Toxicology Adipose capsule of kidney Excretion chemistry.chemical_compound Cytochrome P-450 Enzyme System Cytochrome P-450 CYP1A2 Safrole Internal medicine medicine Animals Bile Cytochrome P-450 Enzyme Inhibitors Toxicokinetics Tissue Distribution heterocyclic compounds reproductive and urinary physiology Dose-Response Relationship Drug biology Chemistry Bile duct CYP1A2 Cytochrome P450 Oxidoreductases N-Demethylating Rats Inbred F344 Rats stomatognathic diseases Endocrinology medicine.anatomical_structure Liver Isosafrole biology.protein Corn Oil Perfusion |
| Zdroj: | Fundamental and Applied Toxicology. 21:405-411 |
| ISSN: | 0272-0590 |
| DOI: | 10.1006/faat.1993.1115 |
| Popis: | Effect of Dose, Time, and Pretreatment on the Biliary Excretion and Tissue Distribution of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in the Rat. Kedderis, L. B., Andersen, M. E., and Birnbaum, L. S. (1993). Fundam. Appl. Toxicol. 21, 405-411. 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 ∼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. The time dependence of factors involved in the dose-related hepatic accumulation of TCDD disposition was illustrated by the elevated liver:fat concentration ratios observed at the 100 versus 10 or 1 nmol/kg dose at 30 hr, but not by 5-6 hr after dosing. In studies designed to evaluate the role of CYP1A2 in the hepatic disposition of TCDD, pretreatment with isosafrole, a selective inhibitor of CYP1A2, diminished hepatic concentrations of [3H]TCDD. In conclusion, TCDD was metabolically cleared at a fairly constant rate over an 80-hr period, and the rate of elimination was proportional with regard to dose. Studies with isosafrole suggest that TCDD is bound to CYP1A2 in the liver. |
| Databáze: | OpenAIRE |
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