17beta-Estradiol up-regulates UDP-glucuronosyltransferase 1A9 expression via estrogen receptor alpha.

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Cho SJ, Ning M, Zhang Y, Rubin LH, Jeong H

17beta-Estradiol up-regulates UDP-glucuronosyltransferase 1A9 expression via estrogen receptor alpha.

Acta Pharm Sin B. 2016 Sep;6(5):504-509. doi: 10.1016/j.apsb.2016.04.005. Epub 2016 May 20.

PubMed ID

27709019 [ View in PubMed

]

Abstract

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 17beta-estradiol (E2) on UGT1A9 expression and the role of ERalpha in the transcriptional regulation of UGT1A9. E2 significantly increased UGT1A9 promoter activity in HepG2 cells in the presence of ERalpha. UGT1A9 induction by E2 was abrogated by antiestrogen ICI182,780 in HepG2 cells that constitutively express ERalpha. Results from transient transfection of ERalpha mutants into HepG2 cells demonstrated that mutation at DNA-binding domain of ERalpha 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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Estradiol	UDP-glucuronosyltransferases (UGTs) (Protein Group)	Protein group	Humans	Unknown	Substrate Inducer	Details