Role of UDP-Glucuronosyltransferase (UGT) 2B2 in Metabolism of Triiodothyronine: Effect of Microsomal Enzyme Inducers in Sprague Dawley and UGT2B2-Deficient Fischer 344 Rats

Microsomal enzyme inducers (MEI) that increase UDP-glucuronosyltransferases (UGTs) can impact thyroid hormone homeostasis in rodents. Increased glucuronidation can result in reduction of serum thyroid hormone and a concomitant increase in thyroid-stimulating hormone (TSH). UGT2B2 is thought to glucu...

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Bibliographic Details
Published in:Toxicological sciences 2010-08, Vol.116 (2), p.413-421
Main Authors: Richardson, Terrilyn A., Klaassen, Curtis D.
Format: Article
Language:English
Subjects:
Androsterone - metabolism
Animals
Biotransformation and Toxicokinetics
Enzyme Induction - drug effects
Glucuronides - metabolism
Glucuronosyltransferase - deficiency
Glucuronosyltransferase - physiology
Male
microsomal enzyme inducers
Microsomes - enzymology
Pregnenolone Carbonitrile - pharmacology
Rats
Rats, Inbred F344
Rats, Sprague-Dawley
Thyroid Gland - drug effects
Thyroid Gland - pathology
thyroid-stimulating hormone
Thyrotropin - blood
Triiodothyronine - metabolism
UDP-glucuronosyltransferase
UGT2B2-deficient Fischer 344 rats
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Summary:Microsomal enzyme inducers (MEI) that increase UDP-glucuronosyltransferases (UGTs) can impact thyroid hormone homeostasis in rodents. Increased glucuronidation can result in reduction of serum thyroid hormone and a concomitant increase in thyroid-stimulating hormone (TSH). UGT2B2 is thought to glucuronidate triiodothyronine (T3). The purposes of this study were to determine the role of UGT2B2 in T3 glucuronidation and whether increased T3 glucuronidation mediates the increased TSH observed after MEI treatment. Sprague Dawley (SD) and UGT2B2-deficient Fischer 344 (F344) 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 thyroxine (T4), T3, and TSH concentrations, hepatic androsterone/T4/T3 glucuronidation, and thyroid follicular cell proliferation were determined. In both SD and F344 rats, MEI treatments decreased serum T4, whereas serum T3 was maintained (except with PCB treatment). Hepatic T4 glucuronidation increased significantly after MEI in both rat strains. Compared with the other MEI, only PCN treatment significantly increased T3 glucuronidation (281 and 497%) in both SD and UGT2B2-deficient F344 rats, respectively, and increased both serum TSH and thyroid follicular cell proliferation. These data demonstrate an association among increases in T3 glucuronidation, TSH, and follicular cell proliferation after PCN treatment, suggesting that T3 is glucuronidated by other PCN-inducible UGTs in addition to UGT2B2. These data also suggest that PCN (rather than 3-MC or PCB) promotes thyroid tumors through excessive TSH stimulation of the thyroid gland.
ISSN:1096-6080
1096-0929
DOI:10.1093/toxsci/kfq125