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 α activation

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

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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 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) α in human hepatocytes and Tg-UGT1 mice. Oral administration of the PPARα 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 PPARα and retinoic acid X receptor α, and functional response of the concatenated PPREs in HepG2 cells overexpressing PPARα. 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.

Original languageEnglish (US)
Pages (from-to)419-427
Number of pages9
JournalDrug Metabolism and Disposition
Volume35
Issue number3
DOIs
StatePublished - Mar 1 2007

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Peroxisome Proliferator-Activated Receptors
Metabolism
Transgenic Mice
Chemical activation
Liver
Acids
Genes
Lithocholic Acid
Pharmaceutical Preparations
Tissue
Gastrointestinal Tract
Fibric Acids
Glucuronosyltransferase
Mutagenesis
Proteins
Retinoic Acid Receptors
Tretinoin
Bile Acids and Salts
Hep G2 Cells
Site-Directed Mutagenesis

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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 α activation. / Senekeo-Effenberger, Kathy; Chen, Shujuan; Brace-Sinnokrak, Erin; Bonzo, Jessica A.; Yueh, Mei Fei; Argikar, Upendra; Kaeding, Jenny; Trottier, Jocelyn; Remmel, Rory P; Ritter, Joseph K.; Barbier, Olivier; Tukey, Robert H.

In: Drug Metabolism and Disposition, Vol. 35, No. 3, 01.03.2007, p. 419-427.

Research output: Contribution to journalArticle

Senekeo-Effenberger, Kathy ; Chen, Shujuan ; Brace-Sinnokrak, Erin ; Bonzo, Jessica A. ; Yueh, Mei Fei ; Argikar, Upendra ; Kaeding, Jenny ; Trottier, Jocelyn ; Remmel, Rory P ; Ritter, Joseph K. ; Barbier, Olivier ; Tukey, Robert H. / 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 α activation. In: Drug Metabolism and Disposition. 2007 ; Vol. 35, No. 3. pp. 419-427.
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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 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) α in human hepatocytes and Tg-UGT1 mice. Oral administration of the PPARα 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 PPARα and retinoic acid X receptor α, and functional response of the concatenated PPREs in HepG2 cells overexpressing PPARα. 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.",
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AU - Chen, Shujuan

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