Stimulation of transcriptional expression of human UDP-glucuronosyltransferase 1A1 by dexamethasone.
Human UDP-glucuronosyltransferase (UGT) 1A1 is only enzyme in the conjugation of bilirubin for prevention of hyperbilirubinemia and jaundice. Deletion or mutation of the UGT1A1 gene causes Crigler-Najjar syndrome or Gilbert's syndrome. We previously reported the functional promoter region for expression of UGT1A1 [Hepatology Research 9, 152-163 (1997)]. We investigated the influence of some drugs on the transient transfection assay of the luciferase reporter gene containing the 5'-promoter region -3174/+14 of UGT1A1 in HepG2 cells. Among drugs investigated, dexamethasone was the most effective at the range of concentration of 10-100 microM, whereas stimulation by beta-estradiol was not found. We also could not find stimulation by bilirubin of the endogenous main substrate for UGT1A1. Stimulation by dexamethasone was continued for 48 hr. The luciferase reporter gene containing the 5'-region of -97/+14 was induced by dexamethasone but the gene of the 5'-region -53/+14 was not. The region -97/-53 is essential for induction by dexamethasone. This region contains HNF1 element, therefore, we speculated that dexamethasone directly and/or indirectly stimulates UGT1A1 expression through this HNF1 region in the promoter region of UGT1A1. Thus, we clarified that UGT1A1 was induced by dexamethasone and the key position was the region (-97/-53) in UGT1A1 promoter.
Kanou
Masanobu
M
Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
Usui
Toru
T
Ueyama
Hisao
H
Sato
Hiroshi
H
Ohkubo
Iwao
I
Mizutani
Takaharu
T
D001483:Base Sequence; D001663:Bilirubin / Q000378:metabolism; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000378:metabolism; D005091:Exons; D017353:Gene Deletion; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000096:biosynthesis*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D000099148:UGT1A1 Enzyme
D001663:Bilirubin; D003907:Dexamethasone; D004958:Estradiol; D005938:Glucocorticoids; D014453:Glucuronosyltransferase; D008156:Luciferases; D000099148:UGT1A1 Enzyme