| Title | Upregulation of UDP-glucuronosyltransferase (UGT) 1A4 by 17{beta}-Estradiol: a Potential Mechanism of Increased Lamotrigine Elimination in Pregnancy. | | Author(s) | Chen H, Yang K, Choi S, Fischer JH, Jeong H | | Institution | University of Illinois at Chicago. | | Source | Drug Metab Dispos 2009 Jun 22. | | Abstract | Oral clearance of lamotrigine, an antiepileptic drug commonly used in pregnant women, is increased in pregnancy by unknown mechanisms. In this study, we show that 17beta-estradiol (E2) upregulates expression of UGT1A4, the major enzyme responsible for elimination of lamotrigine. Endogenous mRNA expression levels of UGT1A4 in estrogen receptor (ER)alpha-negative HepG2 cells were induced 2.3-fold by E2 treatment in the presence of ERalpha expression. E2 enhanced transcriptional activity of UGT1A4 in a concentration-dependent manner in HepG2 cells when ERalpha was co-transfected. Induction of UGT1A4 transcriptional activity by E2 was also observed in ERalpha-positive MCF7 cells, which was abrogated by pretreatment with antiestrogen ICI 182,780. Analysis of UGT1A4 upstream regions using luciferase reporter assays identified a putative Sp1 binding site (-1906 to -1901 bp) that is critical for the induction of UGT1A4 transcriptional activity by E2. Deletion of the Sp1 binding sequence abolished the UGT1A4 upregulation by E2, and Sp1 protein bound to the putative Sp1 binding site as determined by electrophoretic mobility shift assay. Analysis of ERalpha domains using ERalpha mutants revealed that the AF1 and AF2, but not the DNA binding domain, of ERalpha are required for UGT1A4 induction by E2 in HepG2 cells. Finally, E2 treatment increased lamotrigine glucuronidation in ERalpha-transfected HepG2 cells. Together, our data indicate that upregulation of UGT1A4 expression by E2 is mediated by both ERalpha and Sp1, and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19546240 |
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