This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Emi, Y. Articles by Kato, Y. Search for Related Content PubMed PubMed Citation Articles by Emi, Y. Articles by Kato, Y.

Thyroxine-Metabolizing Rat Uridine Diphosphate-Glucuronosyltransferase 1A7 Is Regulated by Thyroid Hormone Receptor

Graduate School of Life Science (Y.E.), University of Hyogo, Harima Science Park City, Hyogo 678-1297, Japan; Biotechnology Research Center (S.I.), Faculty of Engineering, Toyama Prefectural University, Toyama 939-0398, Japan; and Faculty of Pharmaceutical Sciences of Kagawa Campus (Y.K.), Tokushima Bunri University, Kagawa 769-2193, Japan

Address all correspondence and requests for reprints to: Yoshikazu Emi, Graduate School of Life Science, University of Hyogo, Harima Science Park City, Hyogo 678-1297, Japan. E-mail: emys{at}sci.u-hyogo.ac.jp.

Exposure of rats to microsomal enzyme inducers perturbs thyroid hormone (TH) homeostasis through a variety of mechanisms. Glucuronidation is an important metabolic pathway for TH and is catalyzed by uridine diphosphate-dibenzo-glucuronosyltransferase (UGT) family proteins. Administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to rats markedly increases the biliary clearance of glucuronidated T₄ and results in reduced plasma T₄ levels. Determination of the UGT1 isoforms responsible for glucuronidation of T₄ has yet to be conclusively established. We here provide evidence for the involvement of TCDD-inducible UGT1A7 in the glucuronidation of T₄ and TH-controlled UGT1A7 expression. Among a number of rat UGT1 isoenzymes examined in this study, UGT1A7 was the most active in catalyzing glucuronidation of T₄. Expression of UGT1A7 was positively regulated by T₄ through specific binding of TH receptor-retinoid X receptor heterodimers to a DR-5 sequence located between –109 and –93 in the UGT1A7 promoter. Overproduction of UGT1A7 protein decreased T₄ responsiveness of a reporter gene containing the T₄-responsive UGT1A7 promoter sequence. These results raise the possibility that UGT1A7 plays a key role in the glucuronidation of T₄ leading to inactivation of T₄, functioning via feedback regulation to control T₄ levels in an autoregulatory manner, and that T₄ regulates its own metabolism and subsequent clearance from cells. Our findings also predict that accumulation of TCDD-inducible UGT1A7 proteins in TH-target cells might disrupt the TH signaling by lowering the intracellular pool of T₄.

This article has been cited by other articles:

				R. L. Araujo, B. M. de Andrade, A. S. P. de Figueiredo, M. L. da Silva, M. P. Marassi, V. dos Santos Pereira, E. Bouskela, and D. P Carvalho Low replacement doses of thyroxine during food restriction restores type 1 deiodinase activity in rats and promotes body protein loss J. Endocrinol., July 1, 2008; 198(1): 119 - 125. [Abstract] [Full Text] [PDF]