The Effect of Pretreatment on the Biliary Excretion of 2,3,7,8-Tetrachlorodibenzo-p-dioxin, 2,3,7,8-Tetrachlorodibenzofuran, and 3,3′,4,4′-Tetrachlorobiphenyl in the Rat

Abstract The Effect of Pretreatment on the Biliary Excretion of 2,3,7,8-Tetrachlorodibenzo-p-dioxin, 2,3,7,8-Tetrachlorodibenzofuran, and 3,3′,4,4′-Tetrachlorobiphenyl in the rat. McKinley, M. K., Kedderis, L. B., and Birnbaum, L. S. (1993). Fundam. Appl. Toxicol. 21, 425-432. The laterally halogenated chemicals 2,3,7,8-tetrachlorodibenzofuran (TCDF) and 3,3′,4,4′-tetrachlorobiphenyl (TCB) exhibit the same spectrum of toxic effects as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the prototype and most toxic member of the halogenated aromatic hydrocarbon family. Metabolism of all three compounds appears to be the rate-limiting step for excretion, which is primarily via the bile into the feces. Therefore, the biliary elimination of TCDF, TCDD, and TCB was examined as an indirect measure of metabolism. Male F344 rats were anesthetized with pentobarbital, the bile duct was cannulated, and 0.1 μmol [3H]TCDD, [14C]TCDF, or [14C]TCB/kg body wt was administered iv. Bile was collected for 0-8 hr while the animals were kept under anesthesia. To determine if TCDF was able to induce its own metabolism in vivo, a single dose of 1.0 μmol TCDF/kg was administered to rats by oral garage 3 days prior to iv injection of 0.1 or 0.3 μmol [14C]TCDF/kg. Biliary excretion and hepatic concentrations of [14C]TCDF were significantly increased in the pretreated animals. These results suggest an autoinduction of TCDF metabolism. Essentially all biliary [14C]TCDF radioactivity was attributable to metabolites. High-pressure liquid chromatography profiles of biliary radioactivity from 0 to 4 hr were qualitatively different between naive and pretreated rats. To determine if pretreatment with TCDD altered the metabolism of TCDF and vice versa, a single dose of 1.0 μmol TCDF/kg or 0.1 μmol TCDD/kg was administered by oral gavage 3 days prior to iv injection of 0.1 μmol [3H]TCDD or [14C]TCDF/kg, respectively. TCDD pretreatment increased the metabolism and hepatic concentrations of [14C]TCDF in pretreated rats, while biliary elimination and hepatic concentrations of [3H]TCDD were unaffected by pretreatment with TCDF. In a fourth experiment, the ability of TCDD to alter the metabolism of TCB, a laterally substituted polychlorinated biphenyl (PCB), was examined. Pretreatment with TCDD increased the metabolism of [14C]TCB by approximately twofold, but no differences in hepatic concentrations were seen due to the rapid elimination of TCB. Rats pretreated with Aroclor 1254, a commercial mixture of PCBs, demonstrated significantly increased metabolism of [14C]TCB compared to the naive group. Therefore, under these experimental conditions, induction of TCDF metabolism occurred in the rat upon pretreatment with either TCDD or TCDF at doses which also elicited enhanced hepatic uptake. TCDD and Aroclor 1254 induced the metabolism of TCB. These findings suggest that repeated exposure to a chemical or to a mixture of these halogenated aromatic hydrocarbons can result in more rapid metabolism and elimination from the body than following a single, acute exposure.