Received for publication January 8, 2009.
Revised June 16, 2009.
Accepted for publication June 18, 2009.

Upregulation of UDP-glucuronosyltransferase (UGT) 1A4 by 17-Estradiol: a Potential Mechanism of Increased Lamotrigine Elimination in Pregnancy

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 17-estradiol (E2) upregulates expression of UGT1A4, the major enzyme responsible for elimination of lamotrigine. Endogenous mRNA expression levels of UGT1A4 in estrogen receptor (ER)-negative HepG2 cells were induced 2.3-fold by E₂ treatment in the presence of ER expression. E₂ enhanced transcriptional activity of UGT1A4 in a concentration-dependent manner in HepG2 cells when ER was co-transfected. Induction of UGT1A4 transcriptional activity by E2 was also observed in ER-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 ER domains using ER mutants revealed that the AF1 and AF2, but not the DNA binding domain, of ER are required for UGT1A4 induction by E₂ in HepG2 cells. Finally, E₂ treatment increased lamotrigine glucuronidation in ER-transfected HepG2 cells. Together, our data indicate that upregulation of UGT1A4 expression by E₂ is mediated by both ER and Sp1, and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy.

Key words: drug-drug interactions, glucuronidation, hormonal regulation, induction, nuclear receptors, pharmacokinetics, regulation of gene expression, UDP glucuronyltransferases