title: Effect of microsomal enzyme inducers on the biliary excretion of triiodothyronine (T(3)) and its metabolites.
abstract: It has been postulated that inducers of UDP-glucuronosyltransferase (UGT) decrease circulating thyroid hormone concentrations by increasing their biliary excretion. The inducers pregnenolone-16 alpha-carbonitrile (PCN), 3-methylcholanthrene (3MC), and Aroclor 1254 (PCB) are each effective at reducing serum thyroxine concentrations. However, only PCN treatment produces a marked increase in serum levels of thyroid-stimulating hormone (TSH), whereas 3MC and PCB cause little to no increase in TSH. Excessive TSH elevation is considered the primary stimulus for thyroid tumor development in rats, yet the mechanism by which enzyme induction leads to TSH elevation is not fully understood. Whereas PCN, 3MC, and PCB all increase microsomal UGT activity toward T(4), only PCN causes an increase in T(3)-UGT activity in vitro. The purpose of this study was to determine whether PCN, which increases serum TSH, causes an increase in the glucuronidation and biliary excretion of T(3) in vivo. Male rats were fed control diet or diet containing PCN (1000 ppm), 3MC (250 ppm), or PCB (100 ppm) for 7 days. Animals were then given [(125)I]-T(3), i.v., and bile was collected for 2 h. Radiolabeled metabolites in bile were analyzed by reverse-phase HPLC with gamma-detection. The biliary excretion of total radioactivity was increased up to 75% by PCN, but not by 3MC or PCB. Of the T(3) excreted into bile, approximately 75% was recovered as T(3)-glucuronide, with remaining amounts represented as T(3)-sulfate, T(2)-sulfate, T(3), and T(2). Biliary excretion of T(3)-glucuronide was increased up to 66% by PCN, while neither 3MC nor PCB altered T(3)-glucuronide excretion. These findings indicate that PCN increases the glucuronidation and biliary excretion of T(3) in vivo, and suggest that enhanced elimination of T(3) may be the mechanism responsible for the increases in serum TSH caused by PCN.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., 2019 Breidenthal, Kansas City, Kansas 66160-7417, USA.
authors.forename: Nichole R
authors.initials: NR
authors.lastname: Vansell
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004790:Enzyme Induction; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D007457:Iodine Radioisotopes; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014284:Triiodothyronine / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D020719:Glucuronides; D007457:Iodine Radioisotopes; D014284:Triiodothyronine; D020111:Chlorodiphenyl (54% Chlorine); D011285:Pregnenolone Carbonitrile; D008748:Methylcholanthrene; D014453:Glucuronosyltransferase