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题名: UDP-glucuronosyltransferase 1A6 is the major isozyme responsible for protocatechuic aldehyde glucuronidation in human liver microsomes
作者: Liu, Hui-Xin1, 2;  Liu, Yong1;  Zhang, Jiang-Wei1, 2;  Li, Wei1, 2;  Liu, Hong-Tao1, 2;  Yang, Ling1
刊名: DRUG METABOLISM AND DISPOSITION
发表日期: 2008-08-01
DOI: 10.1124/dmd.108.020560
卷: 36, 期:8, 页:1562-1569
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Pharmacology & Pharmacy
研究领域[WOS]: Pharmacology & Pharmacy
英文摘要: Glucuronidation is an important pathway in the metabolism of protocatechuic aldehyde (3,4-dihydroxybenzaldehyde, PAL). However, the metabolites and primary UDP-glucuronosyltransferase (UGT) isozymes responsible for PAL glucuronidation remain to be determined in human. Here, we characterized PAL glucuronidation by human liver microsomes (HLMs), human intestine microsomes (HIMs), and 12 recombinant UGT (rUGT) isozymes to identify what kinds of metabolites are present and which human UGT isozymes are involved. Two metabolites (M-1 and M-2) were detected in reactions catalyzed by HLMs, HIMs, rUGT1A6, and rUGT1A9 and were identified as monoglucuronides by liquid chromatography mass spectrometry. A kinetic study showed that PAL glucuronidation by rUGT1A6, rUGT1A9, HIMs, and HLMs followed Michaelis-Menten kinetics. The Km values of HLMs, HIMs, rUGT1A6, and rUGT1A9 for PAL glucuronidation were as follows: 432.7 +/- 24.5, 626.9 +/- 49.2, 367.5 +/- 25.1, and 379.9 +/- 42.5 +/- mu M for M-1 and 336.7 +/- 15.3, 494.3 +/- 48.7, 211.4 +/- 13.4, and 238.5 +/- 26.2 mu M for M-2, respectively. The PAL glucuronidation activity was significantly correlated with UGT1A6 activity rather than with UGT1A9 activity from 15 individual HLMs. A chemical inhibition study showed that the IC(50) for phenylbutazone inhibition of PAL glucuronidation was similar in HLMs (61.9 +/- 7.9 mu M) compared with rUGT1A6 (45.3 +/- 7.7 mu M). In contrast, androsterone inhibited rUGT1A9-catalyzed and HLM-catalyzed PAL glucuronidation with IC(50) values of 27.1 +/- 3.8 and > 500 mu M, respectively. In combination, we identified UGT1A6 as the major isozyme responsible for PAL glucuronidation in HLMs.
关键词[WOS]: SALVIA-MILTIORRHIZA ;  PHASE-I ;  RAT ;  ACID ;  IDENTIFICATION ;  EXPRESSION ;  UGT1A6 ;  TISSUE ;  EXTRACT ;  DRUG
语种: 英语
WOS记录号: WOS:000257829900016
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/140937
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian 116023, Peoples R China
2.Chinese Acad Sci, Grad Univ, Beijing, Peoples R China

Recommended Citation:
Liu, Hui-Xin,Liu, Yong,Zhang, Jiang-Wei,et al. UDP-glucuronosyltransferase 1A6 is the major isozyme responsible for protocatechuic aldehyde glucuronidation in human liver microsomes[J]. DRUG METABOLISM AND DISPOSITION,2008,36(8):1562-1569.
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