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
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
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DOI：
10.1124/dmd.106.013243d
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发表时间：
2007-03-01
影响因子：
3.9
通讯作者：
Tukey, Robert H.
中科院分区：
文献类型：
--
作者：
Senekeo-Effenberger, Kathy;Chen, Shujuan;Tukey, Robert H.
人类的UDP-葡萄糖醛酸基转移酶(UGT)1A基因已被证明是以组织特有的方式进行差异调控的。携带人类UGT1基因座的转基因小鼠(TG-UGT1)最近被创造出来，证明了9个UGT1A基因的表达与在人类组织中观察到的表达模式非常相似。在本研究中，UGT1A1、UGT1A3、UGT1A4和UGT1A6已被确定为人肝细胞和TG-UGT1小鼠中的PPARα的靶标。口服PPARα激动剂4-chloro-6-(2，3-xylidino)-2-pyrimidinylthioacetic酸(吡尼昔酸，WY-14643)给TG-UGT1小鼠导致肝脏、胃肠道或肾脏中这些蛋白质的诱导。肝脏中诱导的UGT1A3基因转录本和小肠中UGT1A4蛋白的水平与这些组织中诱导的拉莫三嗪葡萄糖醛酸化活性相关。由于UGT1A3以前被认为是参与人的胆石酸(LCA)的C24-葡萄糖醛酸化反应的主要人类酶，在TG-UGT1小鼠体内对肝脏UGT1A3RNA的显著诱导与血浆中LCA-24G的形成是一致的。此外，在高表达PPARα的HepG2细胞中，通过定点突变、与PPARα和维甲酸X受体α的特异性结合以及串联的PPRE的功能反应，鉴定了位于UGT1A1、UGT1A3和UGT1A6基因两侧的PPAR反应元件(PPRE)。总之，这些结果表明，人类口服贝特治疗将在胃肠道和肝脏中诱导UGT1A蛋白家族，影响与降血脂治疗同时服用的其他药物的胆汁酸葡萄糖醛酸化和首过代谢。
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 PPAR alpha 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 PPAR alpha and retinoic acid X receptor alpha, and functional response of the concatenated PPREs 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.