Abstract

The extreme biological persistence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is due primarily to its resistance to metabolic transformation. Previous studies in several species have found hepatic metabolism to be rate-limiting for TCDD elimination, with resulting metabolites excreted primarily in feces via the bile. Using short-term biliary excretion of [³H]TCDD metabolites as an indirect measure of metabolism, groups of F344 rats were used to evaluate separately the effects of age, sex, and acute induction or inhibition of key hepatic enzymes. Adult and juvenile male and female rats were used for sex comparisons, and senescent male rats were used to explore possible changes in TCDD metabolism with age. Various pretreatments were used: phenobarbital (PB) and dexamethasone (DEX), to induce hepatic cytochrome P450 isozymes; and suicide substrate 1-aminobenzotriazole (ABT), to produce P450 inhibition. For all animals, surgical cannulation of the common bile duct and 6-hr bile collection were performed under constant anesthesia. [³H]TCDD (1 nmol/kg) was administered via the femoral vein. Naive adult male and female rats excreted ∼0.7% and ∼0.4% of [³H]TCDD-derived radioactivity, respectively. Biliary excretion of radioactivity in both male and female juvenile rats was similar to that of adult males; senescent male rats excreted less. Pretreatment with PB, DEX, or ABT resulted in similar decrease in biliary excretion of TCDD-derived radioactivity as observed in senescent male rats.