Expression of the human UGT1 locus in transgenic mice by 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY-14643) and implications on drug metabolism through peroxisome proliferator-activated receptor alpha activation
| Autor: | Shujuan Chen, Rory P. Remmel, Upendra A. Argikar, Jessica A. Bonzo, Jocelyn Trottier, Joseph K. Ritter, Robert H. Tukey, Mei-Fei Yueh, Jenny Kaeding, Erin Brace-Sinnokrak, Kathy Senekeo-Effenberger, Olivier Barbier |
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| Rok vydání: | 2006 |
| Předmět: |
Male
medicine.medical_specialty UGT1A4 Lithocholic acid medicine.drug_class Transgene Glucuronidation Retinoic acid Pharmaceutical Science Peroxisome proliferator-activated receptor Mice Transgenic Biology Lamotrigine Gene Expression Regulation Enzymologic Cell Line chemistry.chemical_compound Mice Internal medicine Microsomes medicine Animals Humans PPAR alpha Glucuronosyltransferase Pharmacology chemistry.chemical_classification Bile acid Triazines Molecular biology Gastrointestinal Tract Endocrinology Pyrimidines chemistry Liver Pirinixic Acid Hepatocytes Anticonvulsants Peroxisome Proliferators |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 35(3) |
| ISSN: | 0090-9556 |
| Popis: | 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 nine 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 (PPAR) alpha in human hepatocytes and Tg-UGT1 mice. Oral administration of the PPARalpha agonist 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (pirinixic acid, 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 protein 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 PPARalpha and retinoic acid X receptor alpha, and functional response of the concatenated PPREs in HepG2 cells overexpressing PPARalpha. 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. |
| Databáze: | OpenAIRE |
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