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题名: Diethylstilbestrol can effectively accelerate estradiol-17-O-glucuronidation, while potently inhibiting estradiol-3-O-glucuronidation
作者: Zhu, Liangliang1;  Xiao, Ling1;  Xia, Yangliu2;  Zhou, Kun3;  Wang, Huili1;  Huang, Minyi1;  Ge, Guangbo2;  Wu, Yan1;  Wu, Ganlin1;  Yang, Ling2
关键词: Diethylstilbestrol ;  UGT1A1 ;  UGT1A4 ;  Estradiol glucuronidation
刊名: TOXICOLOGY AND APPLIED PHARMACOLOGY
发表日期: 2015-03-01
DOI: 10.1016/j.taap.2015.01.003
卷: 283, 期:2, 页:109-116
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Pharmacology & Pharmacy ;  Toxicology
研究领域[WOS]: Pharmacology & Pharmacy ;  Toxicology
英文摘要: This in vitro study investigates the effects of diethylstilbestrol (DES), a widely used toxic synthetic estrogen, on estradiol-3- and 17-O- (E2-3/17-0) glucuronidation, via culturing human liver microsomes (HLMs) or recombinant UDP-glucuronosyltransferases (UGTs) with DES and E2. DES can potently inhibit E2-3-O-glucuronidation in HLM, a probe reaction for UGT1A1. Kinetic assays indicate that the inhibition follows a competitive inhibition mechanism, with the Ki value of 2.1 +/- 03 mu M, which is less than the possible in vivo level. In contrast to the inhibition on E2-3-O-glucuronidation, the acceleration is observed on E2-17-O-glucuronidation in HLM, in which cholestatic E2-17-O-glucuronide is generated. In the presence of DES (0-6.25 mu M), K-m values for E2-17-O-glucuronidation are located in the range of 7.2-7.4 mu M, while V-max values range from 0.38 to 1.54 nmol/min/mg. The mechanism behind the activation in HLM is further demonstrated by the fact that DES can efficiently elevate the activity of UGT1A4 in catalyzing E2-17-O-glucuronidation. The presence of DES (2 mu M) can elevate V-max from 0.016 to 0.81 nmol/min/mg, while lifting K-m in a much lesser extent from 4.4 to 11 mu M. Activation of E2-17-O-glucuronidation is well described by a two binding site model, with K-A, alpha, and beta values of 0.077 +/- 0.18 mu M, 33 +/- 1.1 and 104 +/- 56, respectively. However, diverse effects of DES towards E2-3/17-O-glucuronidation are not observed in liver microsomes from several common experimental animals. In summary, this study issues new potential toxic mechanisms for DES: potently inhibiting the activity of UGT1A1 and powerfully accelerating the formation of cholestatic E2-17-O-glucuronide by UGT1A4. (C) 2015 Elsevier Inc. All rights reserved.
关键词[WOS]: GLUCURONOSYLTRANSFERASE UGT 1A4 ;  HEPATIC DRUG GLUCURONIDATION ;  MESSENGER-RNA EXPRESSION ;  UDP-GLUCURONOSYLTRANSFERASES ;  HUMAN LIVER ;  GENETIC-POLYMORPHISM ;  BREAST-CANCER ;  METABOLISM ;  17-BETA-ESTRADIOL ;  CYTOCHROME-P450
语种: 英语
WOS记录号: WOS:000350008300005
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/145938
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.Anqing Normal Univ, Sch Life Sci, Ctr Drug & Food Safety Evaluat, Anqing 246011, Peoples R China
2.Chinese Acad Sci, Dalian Inst Chem Phys, Dalian 116023, Peoples R China
3.Liaoning Univ Tradit Chinese Med, Coll Pharm, Dalian 116600, Peoples R China

Recommended Citation:
Zhu, Liangliang,Xiao, Ling,Xia, Yangliu,et al. Diethylstilbestrol can effectively accelerate estradiol-17-O-glucuronidation, while potently inhibiting estradiol-3-O-glucuronidation[J]. TOXICOLOGY AND APPLIED PHARMACOLOGY,2015,283(2):109-116.
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