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Identification of the UDP-Glucuronosyltransferase Isozyme Involved in Senecionine Glucuronidation in Human Liver Microsomes
He, Yu-Qi1; Liu, Yong2; Zhang, Bin-Feng1; Liu, Hui-Xin2; Lu, Yan-Liu3; Yang, Li1; Xiong, Ai-zhen1; Xu, Ling-Ling1; Wang, Chang-Hong1; Yang, Ling2; Wang, Zheng-Tao1; Wang ZT
Source PublicationDRUG METABOLISM AND DISPOSITION
2010-04-01
DOI10.1124/dmd.109.030460
Volume38Issue:4Pages:626-634
Indexed BySCI
SubtypeArticle
Department18
Funding Project1806
Contribution Rank2;2
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
WOS SubjectPharmacology & Pharmacy
WOS Research AreaPharmacology & Pharmacy
WOS KeywordPYRROLIZIDINE ALKALOIDS ; IN-VITRO ; METABOLIC-ACTIVATION ; SPECIES-DIFFERENCES ; N-GLUCURONIDATION ; MEDICINAL-PLANTS ; UGT2B10 ; RAT ; BILIRUBIN ; NICOTINE
AbstractSenecionine (SEN) is a representative of the hepatotoxic pyrrolizidine alkaloids. Although phase I metabolism for cytochrome P450-mediated metabolic activation of SEN was investigated extensively, phase II metabolism for glucuronidation of this compound has not been investigated until now. In our present study, one unique glucuronidation product of SEN in human liver microsomes (HLMs) was identified as SEN N-glucuronide using an authentically synthesized product for which the structure was identified via (1)H and (13)C NMR analysis. Subsequently, kinetics indicated that SEN N-glucuronidation followed the typical Michaelis-Menten model and only one major isozyme participated in it. Finally, this isozyme was demonstrated to be UDP-glucuronosyltransferase (UGT) 1A4, with the direct evidence that recombinant UGT1A4 exhibited predominant and exclusive activity on SEN N-glucuronidation. This result was confirmed by other experiments including chemical inhibition by selective inhibitors and a correlation study between activities of SEN N-glucuronidation and various UGT isozymes. The exclusive role of UGT1A4 on SEN N-glucuronidation was strengthened additionally by its inhibitory kinetic study in which the selective inhibitor of UGT1A4 showed a similar inhibition pattern and K(i) values in both HLM and recombinant UGT1A4 systems. Because UGT2B10 activity failed to correlate with SEN N-glucuronidation in HLMs from 10 individuals, it was impossible for UGT2B10 to play an important role in this metabolism.
Language英语
URL查看原文
WOS IDWOS:000275670000011
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Cited Times:9[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/103385
Collection中国科学院大连化学物理研究所
Corresponding AuthorWang ZT
Affiliation1.Shanghai Univ Tradit Chinese Med, Inst Chinese Mat Med, MOE Key Lab Standardizat Chinese Med, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Dalian Inst Chem Phys, Dalian, Peoples R China
3.Shanghai Univ Tradit Chinese Med, Affiliated Longhua Hosp, Shanghai, Peoples R China
Recommended Citation
GB/T 7714
He, Yu-Qi,Liu, Yong,Zhang, Bin-Feng,et al. Identification of the UDP-Glucuronosyltransferase Isozyme Involved in Senecionine Glucuronidation in Human Liver Microsomes[J]. DRUG METABOLISM AND DISPOSITION,2010,38(4):626-634.
APA He, Yu-Qi.,Liu, Yong.,Zhang, Bin-Feng.,Liu, Hui-Xin.,Lu, Yan-Liu.,...&Wang ZT.(2010).Identification of the UDP-Glucuronosyltransferase Isozyme Involved in Senecionine Glucuronidation in Human Liver Microsomes.DRUG METABOLISM AND DISPOSITION,38(4),626-634.
MLA He, Yu-Qi,et al."Identification of the UDP-Glucuronosyltransferase Isozyme Involved in Senecionine Glucuronidation in Human Liver Microsomes".DRUG METABOLISM AND DISPOSITION 38.4(2010):626-634.
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