期刊
DRUG METABOLISM AND DISPOSITION
卷 37, 期 9, 页码 1841-1847出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/dmd.109.026609
关键词
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资金
- National Institutes of Health National Institute of Child Health and Human Development [HD055313, K12HK055892]
- National Institutes of Health National Center for Research Resources [C06-RR15482]
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 beta-estradiol (E-2) up-regulates expression of UDP glucuronosyltransferase (UGT) 1A4, 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 E-2 treatment in the presence of ER alpha expression. E-2 enhanced transcriptional activity of UGT1A4 in a concentration-dependent manner in HepG2 cells when ER alpha was cotransfected. Induction of UGT1A4 transcriptional activity by E-2 was also observed in ER alpha-positive MCF7 cells, which was abrogated by pretreatment with the antiestrogen fulvestrant (ICI 182,780). Analysis of UGT1A4 upstream regions using luciferase reporter assays identified a putative specificity protein-1 (Sp1) binding site (-1906 to -1901 base pairs) that is critical for the induction of UGT1A4 transcriptional activity by E-2. Deletion of the Sp1 binding sequence abolished the UGT1A4 up-regulation by E-2, and Sp1 bound to the putative Sp1 binding site as determined by a electrophoretic mobility shift assay. Analysis of ER alpha domains using ER alpha mutants revealed that the activation function (AF) 1 and AF2 domains but not the DNA binding domain of ER alpha are required for UGT1A4 induction by E-2 in HepG2 cells. Finally, E-2 treatment increased lamotrigine glucuronidation in ER alpha-transfected HepG2 cells. Together, our data indicate that up-regulation of UGT1A4 expression by E-2 is mediated by both ER alpha and Sp1 and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy.
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