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

Abstract

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 T(4) and results in reduced plasma T(4) levels. Determination of the UGT1 isoforms responsible for glucuronidation of T(4) has yet to be conclusively established. We here provide evidence for the involvement of TCDD-inducible UGT1A7 in the glucuronidation of T(4) 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 T(4). Expression of UGT1A7 was positively regulated by T(4) 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 T(4) responsiveness of a reporter gene containing the T(4)-responsive UGT1A7 promoter sequence. These results raise the possibility that UGT1A7 plays a key role in the glucuronidation of T(4) leading to inactivation of T(4), functioning via feedback regulation to control T(4) levels in an autoregulatory manner, and that T(4) 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 T(4).