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学科主题: 物理化学
题名: Characterization of Hepatic and Intestinal Glucuronidation of Magnolol: Application of the Relative Activity Factor Approach to Decipher the Contributions of Multiple UDP-Glucuronosyltransferase Isoforms
作者: Zhu, Liangliang1, 2;  Ge, Guangbo1;  Zhang, Hongbo3;  Liu, Huixin1;  He, Guiyuan1, 2;  Liang, Sicheng1;  Zhang, Yanyan1;  Fang, Zhongze1;  Dong, Peipei1;  Finel, Moshe3;  Yang, Ling1
通讯作者: 杨凌
刊名: DRUG METABOLISM AND DISPOSITION
发表日期: 2012-03-01
DOI: 10.1124/dmd.111.042192
卷: 40, 期:3, 页:529-538
收录类别: SCI
文章类型: Article
部门归属: 18
项目归属: 1806
产权排名: 1,1
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: Magnolol is a food additive that is often found in mints and gums. Human exposure to this compound can reach a high dose; thus, characterization of magnolol disposition in humans is very important. Previous studies indicated that magnolol can undergo extensive glucuronidation in humans in vivo. In this study, in vitro assays were used to characterize the glucuronidation pathway in human liver and intestine. Assays with recombinant human UDP-glucuronosyltransferase enzymes (UGTs) revealed that multiple UGT isoforms were involved in magnolol glucuronidation, including UGT1A1, -1A3, -1A7, -1A8, -1A9, -1A10, and -2B7. Magnolol glucuronidation by human liver microsomes (HLM), human intestine microsomes (HIM), and most recombinant UGTs exhibited strong substrate inhibition kinetics. The degree of substrate inhibition was relatively low in the case of UGT1A10, whereas the reaction catalyzed by UGT1A9 followed biphasic kinetics. Chemical inhibition studies and the relative activity factor (RAF) approach were used to identify the individual UGTs that played important roles in magnolol glucuronidation in HLM and HIM. The results indicate that UGT2B7 is mainly responsible for the reaction in HLM, whereas UGT2B7 and UGT1A10 are significant contributors in HIM. In summary, the current study clarifies the glucuronidation pathway of magnolol and demonstrates that the RAF approach can be used as an efficient method for deciphering the roles of individual UGTs in a given glucuronidation pathway in the native tissue that is catalyzed by multiple isoforms with variable and atypical kinetics.
关键词[WOS]: HUMAN LIVER-MICROSOMES ;  DRUG-GLUCURONIDATION ;  SUBSTRATE ;  EXPRESSION ;  CYTOCHROME-P450 ;  SPECIFICITY ;  SELECTIVITY ;  METABOLISM ;  DOPAMINE ;  KINETICS
语种: 英语
WOS记录号: WOS:000300610100017
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/118375
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, Lab Pharmaceut Resource Discovery, Dalian Inst Chem Phys, Dalian 116023, Peoples R China
2.Chinese Acad Sci, Grad Univ, Beijing, Peoples R China
3.Univ Helsinki, Ctr Drug Res, Fac Pharm, Helsinki, Finland

Recommended Citation:
Zhu, Liangliang,Ge, Guangbo,Zhang, Hongbo,et al. Characterization of Hepatic and Intestinal Glucuronidation of Magnolol: Application of the Relative Activity Factor Approach to Decipher the Contributions of Multiple UDP-Glucuronosyltransferase Isoforms[J]. DRUG METABOLISM AND DISPOSITION,2012,40(3):529-538.
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