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Drug Metabolism and Disposition Fast Forward
First published on December 6, 2006; DOI: 10.1124/dmd.106.013243

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Received for publication October 13, 2006.
Revised December 4, 2006.
Accepted for publication December 5, 2006.

Expression of the human UGT1 locus in transgenic mice by WY-14643 and implications on drug metabolism through PPAR{alpha} activation

Kathy Senekeo-Effenberger 1, Shujuan Chen 1, Erin Brace-Sinnokrak 1, Mei-Fei Yueh 1, Jessica A Bonzo 1, Upendra Argikar 2, Jenny Kaeding 3, Jocelyn Trottier 3, Rory P. Remmel 2, Joseph K Ritter 4, Olivier K Barbier 3, Robert H Tukey 1*

1 University of California - San Diego 2 University of Minnesota 3 Laval University 4 Virginia Commonwealth University

* Address correspondence to: E-mail: rtukey{at}ucsd.edu

Abstract

The UDP-glucuronosyltransferase (UGT) 1A genes in humans have been shown to be differentially regulated in a tissue specific fashion. Transgenic mice carrying the human UGT1 locus (Tg-UGT1) were recently created demonstrating that expression of the 9 UGT1A genes closely resembles the patterns of expression observed in human tissues. In the present study, UGT1A1, UGT1A3, UGT1A4 and UGT1A6 have been identified as targets of the peroxisome proliferator-activated receptor alpha (PPAR{alpha}) in human hepatocytes and Tg-UGT1 mice. Oral administration of the PPAR{alpha} agonist WY-14643 to Tg-UGT1 mice led to induction of these proteins in either the liver, gastrointestinal tract or kidney. The levels of induced UGT1A3 gene transcripts in liver and UGT1A4 in small intestine correlated with induced lamotrigine glucuronidation activity in these tissues. With UGT1A3 previously identified as the major human enzyme involved in human C24-glucuronidation of lithocholic acid (LCA), the dramatic induction of liver UGT1A3 RNA in Tg-UGT1 mice was consistent with the formation of LCA-24G in plasma. Furthermore, PPAR responsive elements (PPREs) were identified flanking the UGT1A1, UGT1A3 and UGT1A6 genes by a combination of site directed mutagenesis, specific binding to PPAR{alpha} and RXR{alpha}, and functional response of the concatenated PPRE elements in HepG2 cells overexpressing PPAR{alpha}. In conclusion, these results suggest that oral fibrate treatment in humans will induce the UGT1A family of proteins in the gastrointestinal tract and liver, influencing bile acid glucuronidation and first pass metabolism of other drugs that are taken concurrently with hypolipidemic therapy.


Key words: bile acid metabolism, gene regulation, glucuronidation, peroxisome proliferator-activated receptors, phase II drug metabolism, PXR, SXR, UDP glucuronyltransferases


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