Increased biliary excretion of thyroxine by microsomal enzyme inducers

The extrathyroidal mechanism by which endocrine disruptors promote thyroid tumors has been proposed to be increased glucuronidation and biliary elimin ation of thyroxine (T-4), followed by disruption of the hypothalamic-pituit ary-thyroid axis. The ability of a chemical to increase T-4 glucuronidation in vitro correlates with the ability to reduce serum T-4 concentrations. P regnenolone-16 alpha -carbonitrile (PCN), 3-methylehloranthrene (3-MC), and Aroclor 1254 (PCB) each increase T-4 glucuronidation in rat liver microsom es and reduce serum T-4. However, whether reductions in serum T-4 result di rectly from increases in T-4 glucuronidation and biliary excretion in vivo has not been thoroughly examined. It is also unclear whether reduced serum T-4 concentrations following microsomal enzyme inducer treatment elicit inc reases in serum thyrotropin (TSH), the primary stimulus for thyroid cell pr oliferation, because only PCN treatment increases serum TSH. This study sou ght to determine whether increases in T-4-glucuronide biliary excretion in vivo are responsible for reductions in serum T-4 and increases in serum TSH . Male rats were fed control diet or diet containing either 1000 ppm PCN, 2 50 ppm 3-MC, or 100 ppm PCB for 7 days. Animals were then given [I-125]T-4, and bile was collected for 2 h. Radiolabeled metabolites in bile were anal yzed by reverse-phase HPLC with gamma -detection. PCN, 3-MC, and PCB treatm ents reduced serum T-4 concentrations by 42, 45, and 73%, respectively, whi le TSH was only increased by PCN (180%). The biliary excretion of [I-125]th yronines was increased 103% by PCN, 157% by 3-MC, and 193% by PCB. T-4-gluc uronide was the primary metabolite in bile, accounting for up to 86% of the radiolabeled metabolites in controls. The amount of T-4-glucuronide excret ed in bile was increased 161% and 226% by 3-MC and PCB, respectively, but w as only increased 55% by PCN. None of the treatments had any effect on the urinary excretion of [I-125]T-4. Thus, increased glucuronidation and biliar y excretion of T-4 appears likely to be responsible for reductions in serum T-4 produced by microsomal enzyme inducers. Furthermore, increases in T-4 biliary excretion produced by microsomal enzyme inducer treatment are not c onsistent with changes in TSH. Thus, it can be concluded that differential changes in serum TSH do not stem from differential increases in T-4 biliary excretion. (C) 2001 Academic Press.