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17β‐Estradiol Up‐regulates UGT1A9 Expression via Estrogen Receptor α
Author(s) -
Cho Sungjoon,
Ning Miaoran,
Zhang YanYan,
Rubin Leah,
Jeong Hyunyoung
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1196.6
Subject(s) - estrogen receptor , estrogen , reporter gene , transfection , transcriptional regulation , endogeny , mutant , biology , estrogen receptor alpha , estrogen receptor beta , receptor , transcription factor , gene , chemistry , microbiology and biotechnology , gene expression , endocrinology , genetics , cancer , breast cancer
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 17β‐estradiol (E2) on UGT1A9 expression and the role of estrogen receptor (ER) α in the transcriptional regulation of UGT1A9. E2 significantly increased UGT1A9 promoter activity in HepG2 cells in the presence of ERα. UGT1A9 induction by E2 was abrogated by antiestrogen ICI182,780 in HepG2 cells constitutively expressing ERα. Results from UGT1A9 promoter reporter assays in HepG2 cells transfected with different ERα mutants showed that DNA‐binding domain of ERα is essential in UGT1A9 induction by E2. Deletion and mutation assays of UGT1A9 promoter revealed a putative ERE located within −2262/−1987 region, but electrophoretic mobility assays demonstrated no direct ERα binding to a DNA probe harboring the region. Examination of healthy human liver tissues revealed statistically significant increases in UGT1A9 expression in women (of age < 45 years) as compared to men. Together, these results indicate an important role of estrogen in the regulation of UGT1A9 expression. This finding may shed a light on prediction of potential drug‐drug interaction involving UGT1A9 substrates as well as on identifying sources for inter‐individual variability in UGT1A9‐mediated drug metabolism