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DISPOSITION OF 2,3,7,8-TETRABROMODIBENZO-P-DIOXIN AND 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN IN THE RAT: BILIARY EXCRETION AND INDUCTION OF CYTOCHROMES CYP1A1 AND CYP1A2
Citation:
Kedderis, L., J. Diliberto, P. Linko, J. Goldstein, AND L. Birnbaum. DISPOSITION OF 2,3,7,8-TETRABROMODIBENZO-P-DIOXIN AND 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN IN THE RAT: BILIARY EXCRETION AND INDUCTION OF CYTOCHROMES CYP1A1 AND CYP1A2. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-92/060 (NTIS PB92150747).
Description:
The biologic activity and pharmacokinetic properties of 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) are similar to those of the chlorinated congener, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Metabolism of both compounds appears to be rate-limiting for excretion which is primarily via the feces. Therefore, the biliary elimination of TBDD and TCDD was examined as an indirect assessment of metabolism. Male F344 rats were anesthetized, and 1 nmol/kg [3H]TBDD or [3H]TCDD was administered iv. Bile was collected for up to 8 hrs. The rate of biliary excretion of radioactivity was greater for TCDD than TBDD (10% vs 7% in 5 hrs). All biliary radioactivity was attributable to metabolites. HPLC profiles of biliary radioactivity were similar for [3H]TBDD and [3H]TCDD. To determine if pretreatment altered elimination kinetics, a single dose of 100 nmol/kg TBDD or TCDD was administered to rats by oral gavage 3 days prior to iv injection of 1 nmol/kg [3H]TBDD or [3H]TCDD, respectively. Biliary excretion of radioactivity was quantitatively and qualitatively unaffected by pretreatment despite a 2-fold increase in hepatic levels of radiolabel in the pretreated animals. Therefore, auto-induction of TCDD and TBDD metabolism did not occur in the rat in vivo at doses which elicited enhanced hepatic uptake. In other studies, dose-response profiles for induction of cytochromes P45OIA1 and P45OIA2 by TBDD were characterized. The ED50 value for P45OIA1 induction (measured by ethoxyresorufin O-deethylase activity and radioimmunoassay (RIA) was estimated to be 0.8-1.0 nmol/kg, similar to what has been reported for TCDD. Induction of P45OIA2 (RIA) by TBDD appeared to be a more sensitive response over the dose range studied. Finally, comparison of the dose-response behavior for TBDD induction of hepatic P45OIA2 with hepatic concentrations of TBDD suggested that induction of P45OIA2 alone does not account for nonlinearities n dioxin disposition exemplified by dose-related increases in the ratio of dioxin concentrations in liver and fat.