Effect of Dose, Time, and Pretreatement on the Biliary Excretion and Tissue Distribution of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in the Rat

Effect of Dose, Time, and Pretreatment on the Biliary Excretionand Tissue Distribution of 2,3,7,8-Tetrachlorodibenzo-p-dioxinin 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 dispositionindicated that TCDD did not induce its own metabolic elimination.Pretreatment with TCDD did enhance its hepatic uptake. The presentwork was designed to further examine the effects of dose, time,and pretreatment on the tissue distribution and biliary eliminationof ³H]TCDD. Adult male F-344 rats were administered 0 or 100nmol ¹⁴C]TCDD or ³H]-TCDD/kg body weight po 3 days prior tobile duct cannulation and iv injection of 0 or 1 nmol ³H]TCDDor 1, 10, or 100 nmol ¹⁴C]TCDD/kg. Bile was collected for upto 8 hr while rats were maintained under pentobarbital anesthesia.Biliary TCDD and TCDD metabolites were quantified by liquidscintillation spectrometry. In naive animals which receivedno pretreatment, similar rates of excretion (% dose) were observedfollowing iv administration of 1 nmol ³H]TCDD/kg or 10 or 100nmol ¹⁴C-TCDD/kg. Metabolic elimination of highly purified³H]TCDD (<99%) appeared to be linear with respect to timewith 0.8% of the dose being excreted in the bile over a 5- to8-hr collection period 0 or 24 hr after iv dosing (1, 10, or100 nmol/kg) and 72 hr after oral dosing (100 nmol/kg). In allgroups, higher concentrations of TCDD were found in liver versusfat, and perirenal fat concentrations were elevated relativeto epididymal fat concentrations, probably reflective of theenhanced blood perfusion of the former tissue. Pretreatmentenhanced hepatic concentrations and decreased fat concentrationsof the challenge dose. The time dependence of factors involvedin the dose-related hepatic accumulation of TCDD dispositionwas illustrated by the elevated liver:fat concentration ratiosobserved at the 100 versus 10 or 1 nmol/kg dose at 30 hr, butnot by 5–6 hr after dosing. In studies designed to evaluatethe role of CYP1A2 in the hepatic disposition of TCDD, pretreatmentwith isosafrole, a selective inhibitor of CYP1A2, diminishedhepatic concentrations of ³H]TCDD. In conclusion, TCDD wasmetabolically cleared at a fairly constant rate over an 80-hrperiod, and the rate of elimination was proportional with regardto dose. Studies with isosafrole suggest that TCDD is boundto CYP1A2 in the liver.