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Estrogen receptor‐mediated regulation of UDP‐glucuronosyltransferase (UGT) 1A4 by estrogen
Author(s) -
Jeong Hyunyoung,
Chen Huiqing,
Choi Suyoung,
Fischer James
Publication year - 2008
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.22.1_supplement.921.17
Subject(s) - estrogen , estrogen receptor , transfection , luciferase , endogeny , antiestrogen , estrogen receptor alpha , chemistry , biology , medicine , endocrinology , gene , biochemistry , cancer , breast cancer
The objective of this study is to characterize estrogen‐mediated regulatory mechanisms of UGT1A4, the major enzyme responsible for elimination of lamotrigine, in view of increased oral clearance of lamotrigine in pregnancy and oral contraceptive users. To this end, luciferase promoter reporter assays, semi‐quantitative real‐time (RT)‐PCR, and deletion assays were conducted in HepG2 and MCF7 cells. Treatment of HepG2 cells with estradiol exhibited a concentration‐dependent increase in the activity of UGT1A4 promoter when ERα was co‐transfected. In MCF‐7 cells, pretreatment of the cells with ICI 182,780 (antiestrogen leading to degradation of ERα that are constitutively expressed in MCF‐7 cells) abolished estrogen‐mediated induction of UGT1A4 promoter activity. Endogenous UGT1A4 expression, determined by RT‐PCR, was also induced by 2.3‐fold by estrogen treatment in HepG2 when ERα was co‐transfected. Results from deletion assays in HepG2 cells further indicated that ‐1667 to ‐863 bp region of UGT1A4 promoter is responsible for the ERα‐mediated regulation. In conclusion, the data demonstrate that estrogen positively regulates UGT1A4 expression at the transcriptional level by a mechanism involving ERα. This regulatory mechanism may be responsible for the increased clearance of lamotrigine in pregnancy. The study was supported by University of Illinois at Chicago.