title: Increased biliary excretion of thyroxine by microsomal enzyme inducers.
abstract: The extrathyroidal mechanism by which endocrine disruptors promote thyroid tumors has been proposed to be increased glucuronidation and biliary elimination of thyroxine (T(4)), followed by disruption of the hypothalamic-pituitary-thyroid axis. The ability of a chemical to increase T(4) glucuronidation in vitro correlates with the ability to reduce serum T(4) concentrations. Pregnenolone-16alpha-carbonitrile (PCN), 3-methylchloranthrene (3-MC), and Aroclor 1254 (PCB) each increase T(4) glucuronidation in rat liver microsomes and reduce serum T(4). However, whether reductions in serum T(4) result directly 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 increases in serum thyrotropin (TSH), the primary stimulus for thyroid cell proliferation, because only PCN treatment increases serum TSH. This study sought 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, 250 ppm 3-MC, or 100 ppm PCB for 7 days. Animals were then given [(125)I]T(4) iv, and bile was collected for 2 h. Radiolabeled metabolites in bile were analyzed by reverse-phase HPLC with gamma-detection. PCN, 3-MC, and PCB treatments reduced serum T(4) concentrations by 42, 45, and 73%, respectively, while TSH was only increased by PCN (180%). The biliary excretion of [(125)I]thyronines was increased 103% by PCN, 157% by 3-MC, and 193% by PCB. T(4)-glucuronide was the primary metabolite in bile, accounting for up to 86% of the radiolabeled metabolites in controls. The amount of T(4)-glucuronide excreted in bile was increased 161% and 226% by 3-MC and PCB, respectively, but was only increased 55% by PCN. None of the treatments had any effect on the urinary excretion of [(125)I]T(4). Thus, increased glucuronidation and biliary 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 consistent 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.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160-7140, USA.
authors.forename: N R
authors.initials: NR
authors.lastname: Vansell
authors.forename: C D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology; D001646:Bile / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology; D020719:Glucuronides / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects*; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood / Q000378:metabolism* / Q000652:urine
chemical_list: D013956:Antithyroid Agents; D002273:Carcinogens; D020719:Glucuronides; D020111:Chlorodiphenyl (54% Chlorine); D011285:Pregnenolone Carbonitrile; D008748:Methylcholanthrene; D013972:Thyrotropin; D013974:Thyroxine