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Diethylstilbestrol can effectively accelerate estradiol-17-O-glucuronidation, while potently inhibiting estradiol-3-O-glucuronidation
Zhu, Liangliang1; Xiao, Ling1; Xia, Yangliu2; Zhou, Kun3; Wang, Huili1; Huang, Minyi1; Ge, Guangbo2; Wu, Yan1; Wu, Ganlin1; Yang, Ling2
KeywordDiethylstilbestrol Ugt1a1 Ugt1a4 Estradiol Glucuronidation
Source PublicationTOXICOLOGY AND APPLIED PHARMACOLOGY
2015-03-01
DOI10.1016/j.taap.2015.01.003
Volume283Issue:2Pages:109-116
Indexed BySCI
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
WOS SubjectPharmacology & Pharmacy ; Toxicology
WOS Research AreaPharmacology & Pharmacy ; Toxicology
WOS KeywordGLUCURONOSYLTRANSFERASE UGT 1A4 ; HEPATIC DRUG GLUCURONIDATION ; MESSENGER-RNA EXPRESSION ; UDP-GLUCURONOSYLTRANSFERASES ; HUMAN LIVER ; GENETIC-POLYMORPHISM ; BREAST-CANCER ; METABOLISM ; 17-BETA-ESTRADIOL ; CYTOCHROME-P450
AbstractThis 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.
Language英语
WOS IDWOS:000350008300005
Citation statistics
Cited Times:15[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/145938
Collection中国科学院大连化学物理研究所
Affiliation1.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
GB/T 7714
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.
APA Zhu, Liangliang.,Xiao, Ling.,Xia, Yangliu.,Zhou, Kun.,Wang, Huili.,...&Yang, Ling.(2015).Diethylstilbestrol can effectively accelerate estradiol-17-O-glucuronidation, while potently inhibiting estradiol-3-O-glucuronidation.TOXICOLOGY AND APPLIED PHARMACOLOGY,283(2),109-116.
MLA Zhu, Liangliang,et al."Diethylstilbestrol can effectively accelerate estradiol-17-O-glucuronidation, while potently inhibiting estradiol-3-O-glucuronidation".TOXICOLOGY AND APPLIED PHARMACOLOGY 283.2(2015):109-116.
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