Disruption of thyroid hormone homeostasis in Ugt1a-deficient Gunn rats by microsomal enzyme inducers is not due to enhanced thyroxine glucuronidation

• Published in: Toxicology and applied pharmacology 2010-10, Vol.248 (1), p.38-44
• Main Authors: Richardson, Terrilyn A., Klaassen, Curtis D.
• Format: Article
• Language: English
• Subjects: 3-METHYLCHOLANTHRENE; AMINO ACIDS; ANIMAL CELLS; ANIMALS; Anticonvulsants. Antiepileptics. Antiparkinson agents; Aroclor 1254; AROMATICS; Biological and medical sciences; BODY; CARBOXYLIC ACIDS; CELL PROLIFERATION; Cell Proliferation - drug effects; Chlorodiphenyl (54% Chlorine) - toxicity; CONDENSED AROMATICS; ENDOCRINE GLANDS; ENZYMES; GLANDS; Glucuronosyltransferase - drug effects; Glucuronosyltransferase - metabolism; HOMEOSTASIS; HORMONES; HYDROCARBONS; Liver - drug effects; Liver - metabolism; Male; MAMMALS; Medical sciences; Methylcholanthrene - toxicity; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; MORPHOLOGICAL CHANGES; Neuropharmacology; ORGANIC ACIDS; ORGANIC COMPOUNDS; ORGANIC HALOGEN COMPOUNDS; ORGANIC IODINE COMPOUNDS; ORGANS; PEPTIDE HORMONES; Pharmacology. Drug treatments; Phenobarbital; PITUITARY HORMONES; POLYCYCLIC AROMATIC HYDROCARBONS; Pregnenolone Carbonitrile - toxicity; Pregnenolone-16α-carbonitrile; PROTEINS; RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; RATS; Rats, Gunn; Rats, Wistar; RODENTS; SOMATIC CELLS; THYROID; THYROID CELLS; Thyroid Gland - drug effects; Thyroid Gland - enzymology; THYROID HORMONES; Thyroid stimulating hormone; Thyrotropin - blood; THYROXINE; Thyroxine - drug effects; Thyroxine - metabolism; Thyroxine T 4; Toxicology; Triiodothyronine - blood; TSH; UDP-glucuronosyltransferases, Ugt1a-deficeint Gunn rat; VERTEBRATES
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2010.07.010

Microsomal enzyme inducers (MEI) that increase UDP-glucuronosyltransferases (UGTs) are thought to increase glucuronidation of thyroxine (T 4), thus reducing serum T 4, and subsequently increasing thyroid stimulating hormone (TSH). Ugt1a1 and Ugt1a6 mediate T 4 glucuronidation. Therefore, this experiment determined the involvement of Ugt1a enzymes in increased T 4 glucuronidation, decreased serum T 4, and increased TSH after MEI treatment. Male Wistar and Ugt1a-deficient Wistar (Gunn) rats were fed a control diet or diet containing pregnenolone-16α-carbonitrile (PCN; 800 ppm), 3-methylcholanthrene (3-MC; 200 ppm), or Aroclor 1254 (PCB; 100 ppm) for 7 days. Serum T 4, triiodothyronine (T 3), and TSH concentrations, hepatic T 4/T 3 glucuronidation, and thyroid histology and follicular cell proliferation were investigated. PCN, 3-MC, and PCB treatments decreased serum T 4, whereas serum T 3 was maintained in both Gunn and Wistar rats (except for PCB treatment). TSH was increased in Wistar and Gunn rats after PCN (130 and 277%) or PCB treatment (72 and 60%). T 4 glucuronidation in Wistar rats was increased after PCN (298%), 3-MC (85%), and PCB (450%), but was extremely low in Gunn rats, and unchanged after MEI. T 3 glucuronidation was increased after PCN (121%) or PCB (58%) in Wistar rats, but only PCN increased T 3 glucuronidation in Gunn rats (43%). PCN treatment induced thyroid morphological changes and increased follicular cell proliferation in both strains. These data demonstrate that T 4 glucuronidation cannot be increased in Ugt1a-deficient Gunn rats. Thus, the decrease in serum T 4, increase in TSH, and increase in thyroid cell proliferation after MEI are not dependent on increased T 4 glucuronidation, and cannot be attributed to Ugt1a enzymes.