DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on October 18, 2006; DOI: 10.1124/dmd.106.012203

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.106.012203v1
35/1/116    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gardner-Stephen, D. A
Right arrow Articles by MacKenzie, P. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gardner-Stephen, D. A
Right arrow Articles by MacKenzie, P. I.


Received for publication August 3, 2006.
Revised October 16, 2006.
Accepted for publication October 17, 2006.

Isolation of the UDP glucuronosyltransferase 1A3 and 1A4 proximal promoters and characterization of their dependence on the transcription factor hepatocyte nuclear factor 1 alpha

Dione A Gardner-Stephen 1 Peter Ian MacKenzie 2*

1 Flinders University 2 Flinders University School of Medicine

* Address correspondence to: E-mail: peter.mackenzie{at}flinders.edu.au

Abstract

The UGT1A3-1A5 genes are a highly related UDP-glucuronosyltransferase (UGT) cluster, exhibiting high levels of coding and regulatory region homology. However, the ensuing proteins have both differing substrate specificities and differing expression patterns. The expression profile of each enzyme also varies considerably from one individual to the next. Differences in UGT expression have been predicted to contribute to an individual's response to pharmaceuticals, and to predisposition towards cancer in the event of carcinogen exposure. Therefore, it is desirable to elucidate the mechanisms that drive the transcription of UGT genes and identify the factors responsible for their variable expression. To this end we have isolated the UGT1A3, UGT1A4 and UGT1A5 proximal promoters and begun to investigate the regulatory elements necessary for activity in vitro. We have established that the nucleotide sequence upstream of the UGT1A5 exon 1 is an ineffective promoter, correlating with the lack of substantial expression of this UGT in human tissues. In contrast, the UGT1A3 and UGT1A4 proximal promoters are both highly active in hepatic and colonic cell lines, with maximal activity being encoded by the proximal 500 bp. However, the UGT1A3 and UGT1A4 promoters exhibit low activity in the human embryonic kidney cell line HEK293, unless co-expressed with hepatocyte nuclear factor (HNF) 1{alpha}. Furthermore, mutation of the consensus-like HNF1-binding site in the UGT1A3 promoter abolishes promoter function in all cell types. This study suggests an important role for HNF1{alpha} in the transcriptional regulation of the human UGT1A3 and UGT1A4 genes.


Key words: gene regulation, genetic polymorphism, genotype, UDP glucuronyltransferases


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
D. Zhang, D. Zhang, D. Cui, J. Gambardella, L. Ma, A. Barros, L. Wang, Y. Fu, S. Rahematpura, J. Nielsen, et al.
Characterization of the UDP Glucuronosyltransferase Activity of Human Liver Microsomes Genotyped for the UGT1A1*28 Polymorphism
Drug Metab. Dispos., December 1, 2007; 35(12): 2270 - 2280.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.