Document Detail

The effects of clobazam treatment in rats on the expression of genes and proteins encoding glucronosyltransferase 1A/2B (UGT1A/2B) and multidrug resistance-associated protein-2 (MRP2), and development of thyroid follicular cell hypertrophy.
MedLine Citation:
PMID:  22982618     Owner:  NLM     Status:  MEDLINE    
Clobazam (CLB) is known to increase hepatobiliary thyroxine (T4) clearance in Sprague-Dawley (SD) rats, which results in hypothyroidism followed by thyroid follicular cell hypertrophy. However, the mechanism of the acceleration of T4-clearance has not been fully investigated. In the present study, we tried to clarify the roles of hepatic UDP-glucronosyltransferase (UGT) isoenzymes (UGT1A and UGT2B) and efflux transporter (multidrug resistance-associated protein-2; MRP2) in the CLB-induced acceleration of T4-clearance using two mutant rat strains, UGT1A-deficient mutant (Gunn) and MRP2-deficient mutant (EHBR) rats, especially focusing on thyroid morphology, levels of circulating hormones (T4 and triiodothyronine (T3)) and thyroid-stimulating hormone (TSH), and mRNA or protein expressions of UGTs (Ugt1a1, Ugt1a6, and Ugt2b1/2) and MRP2 (Mrp). CLB induced thyroid morphological changes with increases in TSH in SD and Gunn rats, but not in EHBR rats. T4 was slightly decreased in SD and Gunn rats, and T3 was decreased in Gunn rats, whereas these hormones were maintained in EHBR rats. Hepatic Ugt1a1, Ugt1a6, Ugt2b1/2, and Mrp2 mRNAs were upregulated in SD rats. In Gunn rats, UGT1A mRNAs (Ugt1a1/6) and protein levels were quite low, but UGT2B mRNAs (Ugt2b1/2) and protein were prominently upregulated. In SD and Gunn rats, MRP2 mRNA and protein were upregulated to the same degree. These results suggest that MRP2 is an important contributor in development of the thyroid cellular hypertrophy in CLB-treated rats, and that UGT1A and UGT2B work in concert with MRP2 in the presence of MRP2 function to enable the effective elimination of thyroid hormones.
Izuru Miyawaki; Akitoshi Tamura; Izumi Matsumoto; Hiroshi Inada; Takeshi Kunimatsu; Juki Kimura; Hitoshi Funabashi
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Publication Detail:
Type:  Journal Article     Date:  2012-09-12
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  265     ISSN:  1096-0333     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-03     Completed Date:  2013-04-24     Revised Date:  2014-03-28    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  351-9     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
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MeSH Terms
Anticonvulsants / pharmacology*
Benzodiazepines / pharmacology*
Gene Expression / drug effects
Glucuronosyltransferase / biosynthesis,  genetics*,  metabolism
Isoenzymes / biosynthesis,  genetics,  metabolism
Multidrug Resistance-Associated Proteins / biosynthesis,  genetics*,  metabolism
RNA, Messenger / biosynthesis,  genetics
Random Allocation
Rats, Gunn
Rats, Sprague-Dawley
Real-Time Polymerase Chain Reaction
Thyroid Gland / drug effects*,  enzymology,  metabolism,  pathology*
Thyroid Hormones / blood,  metabolism
Reg. No./Substance:
0/Anticonvulsants; 0/Isoenzymes; 0/Multidrug Resistance-Associated Proteins; 0/RNA, Messenger; 0/Thyroid Hormones; 0/multidrug resistance-associated protein 2; 12794-10-4/Benzodiazepines; 2MRO291B4U/clobazam; EC 2.4.1.-/UGT1A1 enzyme; EC

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