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Induction of UGT1A genes by the fibrate WY‐14643 in Tg‐UGT1 mice and identification of peroxisome proliferator activated receptor (PPAR) responsive elements on the UGT1A1 and UGT1A4 promoters
Author(s) -
BraceSinnokrak Erin J,
SenekeoEffenberger Kathy,
Chen Shujuan,
Tukey Robert H
Publication year - 2007
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.21.6.lb78-a
Subject(s) - fibrate , enhancer , peroxisome proliferator activated receptor , biology , transcription factor , response element , receptor , reporter gene , transfection , promoter , gene , microbiology and biotechnology , medicine , endocrinology , chemistry , biochemistry , gene expression , statin
The UGT1 enzymes are an essential part of drug metabolism and detoxification. A transgenic mouse model expressing all nine functional UGT1A genes was created (Tg‐ UGT1 ) and we have shown that the enzymes are induced by many of the nuclear receptors. The PPARs are activated by hypolipidemic fibrate drugs. The fibrate drug WY‐14643 (WY) was administered orally to Tg‐ UGT1 mice and induced UGT1A1, 1A3, 1A4, 1A6, and 1A9. A DR1 element was identified in the UGT1A1 enhancer: serial deletion of the enhancer and mutation of the DR1 element identified it as essential for WY induction of UGT1A1 . Induction of UGT1A4 protein was observed extrahepatically following WY treatment. The 5kb UGT1A4 enhancer was cloned into a reporter vector. Serial deletion and transfection in LS180 cells identified a region of the promoter responsive to WY. A concatenated DR1 element within this region was induced by WY. These results show that UGT1A genes are induced following PPARα activation by fibrates via DR1 elements on the 3′ enhancers. Induction of these genes may impact the metabolism of these and other drugs and affect drug‐drug interactions in patients on fibrate therapy. (Supported by USPHS Grants ES10337, GM49135)