Functions and transcriptional regulation of adult human hepatic UDP-glucuronosyl-transferases (UGTs): Mechanisms responsible for interindividual variation of UGT levels
Functions and transcriptional regulation of adult human hepatic UDP-glucuronosyl-transferases (UGTs): Mechanisms responsible for interindividual variation of UGT levels
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DOI：
10.1016/j.bcp.2010.04.034
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发表时间：
2010-09-15
影响因子：
5.8
通讯作者：
Bock, Karl Walter
中科院分区：
文献类型：
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作者：
Bock, Karl Walter
19 种 UDP-葡萄糖醛酸基转移酶 (UGT) 中有 10 种在成人肝脏中大量表达（> 总 UGT 的 1%）、5 种 UGT1 亚型（UGT1A1、1A3、1A4、1A6 和 1A9）和 5 种 UGT2 家族成员（UGT2B4、2B7、2B10、2B15 和 2B17） （Izukawa 等人 [11]）令人惊讶的是，UGT2B4 和 UGT2B10 mRNA 在人类肝脏中含量丰富，表明肝脏在其主要底物、胆汁酸和二十烷酸解毒中的作用被低估。在导致肝脏 UGT 水平个体间高度变异的因素中（遗传多样性，包括多态性和剪接变体、肝脏富集转录因子（如 HNF1 和 HNF4）和配体激活转录因子的调节），核受体（PXR、CAR、PPAR α 等）和 Ah 受体进行了讨论。揭示 UGT 表达个体间变异的机制将有利于药物治疗，但仍然是一个重大挑战 (C) 2010 Elsevier Inc 保留所有权利
Ten out of 19 UDP-glucuronosyltransferases (UGTs) are substantially expressed in adult human liver (>1% of total UGTs), 5 UGT1 isoforms (UGT1A1, 1A3, 1A4, 1A6 and 1A9) and 5 UGT2 family members (UGT2B4, 2B7, 2B10, 2B15 and 2B17) (Izukawa et al [11]) Surprisingly, UGT2B4 and UGT2B10 mRNA were found to be abundant in human liver suggesting an underestimated role of the liver in detoxification of their major substrates, bile acids and eicosanolds. Among factors responsible for high interindividual variation of hepatic UGT levels (genetic diversity including polymorphisms and splice variants, regulation by liver-enriched transcription factors such as HNF1 and HNF4. and ligand-activated transcription factors) nuclear receptors (PXR. CAR. PPAR alpha, etc), and the Ah receptor are discussed. Unraveling the mechanisms responsible for interindividual variation of UGT expression will be beneficial for drug therapy but still remains a major challenge (C) 2010 Elsevier Inc All rights reserved