Cho Sung-Joon, Ning Miaoran, Zhang Yanyan, Rubin Leah H, Jeong Hyunyoung
Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, USA.
Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, USA.
Acta Pharm Sin B. 2016 Sep;6(5):504-509. doi: 10.1016/j.apsb.2016.04.005. Epub 2016 May 20.
UDP-glucuronosyltransferase 1A9 (UGT1A9) is a major phase II enzyme responsible for elimination of drugs and endogenous molecules. Clinical data have shown increased elimination of UGT1A9 substrates in pregnant women or oral contraceptive users, but the role of estrogen in the regulation of UGT1A9 expression remains unknown. In this study, we investigated the effect of 17-estradiol (E2) on UGT1A9 expression and the role of ER in the transcriptional regulation of UGT1A9. E2 significantly increased UGT1A9 promoter activity in HepG2 cells in the presence of ER. UGT1A9 induction by E2 was abrogated by antiestrogen ICI182,780 in HepG2 cells that constitutively express ER. Results from transient transfection of ER mutants into HepG2 cells demonstrated that mutation at DNA-binding domain of ER abrogates increased UGT1A9 promoter activity by E2. Deletion and mutation assays of UGT1A9 promoter revealed a putative ERE located within -2262/-1987 region. Examination of healthy human liver tissues revealed significantly higher UGT1A9 expression in women as compared to men. Together, these findings provide a mechanistic basis for the previous clinical reports and may shed a light on identifying sources for inter-individual variability in UGT1A9-mediated drug metabolism.
尿苷二磷酸葡萄糖醛酸基转移酶1A9（UGT1A9）是一种主要的Ⅱ相酶，负责药物和内源性分子的清除。临床数据表明，孕妇或口服避孕药使用者体内UGT1A9底物的清除增加，但雌激素在UGT1A9表达调控中的作用仍不清楚。在本研究中，我们研究了17-β-雌二醇（E2）对UGT1A9表达的影响以及雌激素受体（ER）在UGT1A9转录调控中的作用。在存在ER的情况下，E2显著增加了HepG2细胞中UGT1A9启动子的活性。在组成性表达ER的HepG2细胞中，抗雌激素ICI182,780消除了E2对UGT1A9的诱导作用。将ER突变体瞬时转染到HepG2细胞中的结果表明，ER DNA结合结构域的突变消除了E2对UGT
