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学科主题: 物理化学
题名: Characterization of UDP-Glucuronosyltransferases Involved in Glucuronidation of Diethylstilbestrol in Human Liver and Intestine
作者: Zhu, Liangliang1, 2;  Ge, Guangbo1;  Liu, Yong1;  Guo, Zhimou1;  Peng, Chengcheng1;  Zhang, Feng3;  Cao, Yunfeng1;  Wu, Jingjing1;  Fang, Zhongze1, 2;  Liang, Xinmiao1;  Yang, Ling1
通讯作者: 杨凌
刊名: CHEMICAL RESEARCH IN TOXICOLOGY
发表日期: 2012-12-01
DOI: 10.1021/tx300310k
卷: 25, 期:12, 页:2663-2669
收录类别: SCI
文章类型: Article
部门归属: 18
项目归属: 1806;1803
产权排名: 1,1
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine ;  Physical Sciences
类目[WOS]: Chemistry, Medicinal ;  Chemistry, Multidisciplinary ;  Toxicology
研究领域[WOS]: Pharmacology & Pharmacy ;  Chemistry ;  Toxicology
英文摘要: Diethylstilbestrol (DES), a synthetic estrogen, is famous for its carcinogenic effects. Human exposure to this compound can occur frequently through dietary ingestion and medical treatment. Glucuronidation has been demonstrated to be a predominant metabolic pathway for DES in human. Therefore, glucuronidation metabolism may have a significant impact on its toxicities, and it is essential to clarify this metabolic pathway. Accordingly, this in vitro study is designed to characterize the UGTs involved in DES glucuronidation and, furthermore, to identify the roles of individual isoforms in the reaction in liver and intestine. Human liver microsomes (HLM) displayed much higher potential for DES glucuronidation than human intestinal microsomes (HIM). The intrinsic clearances in HLM and HIM were demonstrated to be 459 and 14 mu L/min/mg protein, respectively. Assays with recombinant UGTs demonstrated that UGT1A1, -1A3, -1A8, and -2B7 could catalyze DES glucuronidation, among which UGT2B7 showed the highest affinity. Chemical inhibitors of UGT2B7 and UGT1A1/1A3 both displayed similar inhibition against the reaction in UGT2B7 and HLM. In addition, DES glucuronidation in individual HLM exhibited a large individual variability and strongly correlated to UGT2B7 activity. All evidence indicates that UGT2B7 may act as a major enzyme responsible for DES glucuronidation in human liver. For HIM, both UGT2B7 inhibitor and UGT1A1/1A3/1A8 inhibitor exerted moderate inhibition. It is suggested that although UGT2B7 contributes to DES glucuronidation in intestine, other UGTs may contribute equally. In summary, this study characterizes human UGTs involved in DES glucuronidation in human liver and intestine, which may be helpful for further study about DES-related toxicities.
关键词[WOS]: HEPATIC DRUG GLUCURONIDATION ;  CANCER ;  WOMEN ;  MECHANISM ;  PREGNANCY ;  EXPOSURE ;  PROSTATE ;  LESSONS ;  ADULT ;  FETAL
语种: 英语
WOS记录号: WOS:000312360500006
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/118322
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, Dalian 116023, Peoples R China
2.Chinese Acad Sci, Grad Sch, Beijing 100049, Peoples R China
3.Chinese Acad Inspect & Quarantine, Beijing 100123, Peoples R China

Recommended Citation:
Zhu, Liangliang,Ge, Guangbo,Liu, Yong,et al. Characterization of UDP-Glucuronosyltransferases Involved in Glucuronidation of Diethylstilbestrol in Human Liver and Intestine[J]. CHEMICAL RESEARCH IN TOXICOLOGY,2012,25(12):2663-2669.
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