Structure-activity relationship analysis of perfluoroalkyl carbonic acids on human and rat placental 3β-hydroxysteroid dehydrogenase activity.

doi:10.1016/j.tox.2022.153334

科研成果详情

题名	Structure-activity relationship analysis of perfluoroalkyl carbonic acids on human and rat placental 3β-hydroxysteroid dehydrogenase activity.
作者	Wang, Shaowei1,3; Zhang, Bingru2; Zhai, Yingna1; Tang, Yunbing1; Lou, Yuzhen 1; Zhu, Yang 2; Wang, Yiyan2; Ge, Ren-shan1,3; Li, Huitao1,3
发表日期	2022-10
发表期刊	Toxicology 影响因子和分区
语种	英语
原始文献类型	Article
关键词	3β-hydroxysteroid dehydrogenase 1/steroid Δ(5,4)-isomerase Mixed inhibitors Perfluoroalkyl carbonic acids Pregnenolone Progesterone
其他关键词	HUMAN TYPE-1 ; PERFLUOROOCTANOIC ACID ; INHIBITION ; CATALYSIS ; CHEMICALS ; SAMPLES ; PLASMA ; TRENDS ; JAPAN
摘要	Placenta contains 3β-hydroxysteroid dehydrogenase/steroid Δ5,4-isomerase (HSD3B), which catalyzes pregnenolone to progesterone for maintaining pregnancy. Perfluoroalkyl carbonic acids (PFC) are subclass of perfluoroalkyl substances containing 4-14 carbons (C4-C14) in the carbon backbone and are potential endocrine disruptors. Whether PFC inhibit HSD3B and structure-activity relationship (SAR) remains unclear. Herein, we screened 11 PFC for inhibiting human type I HSD3B (HSD3B1) and rat type IV HSD3B (HSD3B4) activities and determined SAR and mode of inhibition. HSD3B was measured by converting pregnenolone to progesterone assisted by NAD+ in placental microsomes. Of the 11 PFC, C9-C14 significantly inhibited human HSD3B1 activity at 100 μM. Half-maximal inhibitory concentration (IC50) values of C9-C14 compounds were 363.56 ± 12.14, 12.78 ± 0.69, 6.54 ± 0.65, 20.88 ± 0.41, 118.35 ± 0.16, and 149.26 ± 21.67 μM, respectively. We determined Ki values and mode of inhibition of three most potent PFC (C10-C12), and found that they were mixed inhibitors against pregnenolone, with Ki values of 5.57 ± 4.37, 2.04 ± 2.26, and 9.93 ± 7.71, respectively. Docking analysis showed that they bound steroid-binding site. Effects of PFC on rat placental HSD3B4 were performed. Of the 11 PFC, C10-C12 significantly inhibited rat HSD3B4 activity at 100 μM. IC50 values of C10-C12 compounds were 45.85 ± 1.49, 36.08 ± 1.50, and 88.74 ± 1.99 µM, respectively. Ki values and inhibition modes of the three most potent PFC (C10-C12) were studied. It was found that they were mixed inhibitors against pregnenolone, with Ki values of 48.16 ± 20.44, 36.28 ± 53.07, and 91.79 ± 21.75 μM, respectively. Docking analysis showed that they bound steroid-binding site of rat HSD3B4. In conclusion, PFC showed significant SAR differences. The potency of inhibiting HSD3B activity increased from C9 to C11, and then declined. Human HSD3B1 was more sensitive to the inhibition of rat HSD3B4
资助项目	Health and Family Planning Commission of Zhejiang Province; [11-CX29]
出版者	ELSEVIER IRELAND LTD
出版地	CLARE
ISSN	0300-483X
EISSN	1879-3185
卷号	480 页码:153334
DOI	10.1016/j.tox.2022.153334
页数	11
WOS类目	Pharmacology & Pharmacy ; Toxicology
WOS研究方向	Pharmacology & Pharmacy ; Toxicology
WOS记录号	WOS:000862686500005
收录类别	PUBMED ; SCIE ; SCOPUS
URL	查看原文
PubMed ID	36122607
SCOPUSEID	2-s2.0-85138505384
通讯作者地址	[Ge, Ren-shan]Department of Obstetrics and Gynecology,the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University,Zhejiang,Wenzhou,325027,China
Scopus学科分类	Toxicology
引用统计	被引频次[WOS]：0 [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/166682
专题	第二临床医学院，附属第二医院、育英儿童医院
通讯作者	Ge, Ren-shan
作者单位	1.Department of Obstetrics and Gynecology,the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University,Zhejiang,Wenzhou,325027,China; 2.Department of Anaesthesiology,the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University,Zhejiang,Wenzhou,325027,China; 3.Key Laboratory of Structural Malformations in Children of Zhejiang Province,Zhejiang Province,Wenzhou,325000,China
第一作者单位	第二临床医学院，附属第二医院、育英儿童医院
通讯作者单位	第二临床医学院，附属第二医院、育英儿童医院
第一作者的第一单位	第二临床医学院，附属第二医院、育英儿童医院
推荐引用方式 GB/T 7714	Wang, Shaowei,Zhang, Bingru,Zhai, Yingna,et al. Structure-activity relationship analysis of perfluoroalkyl carbonic acids on human and rat placental 3β-hydroxysteroid dehydrogenase activity.[J]. Toxicology,2022,480:153334.
APA	Wang, Shaowei., Zhang, Bingru., Zhai, Yingna., Tang, Yunbing., Lou, Yuzhen., ... & Li, Huitao. (2022). Structure-activity relationship analysis of perfluoroalkyl carbonic acids on human and rat placental 3β-hydroxysteroid dehydrogenase activity.. Toxicology, 480, 153334.
MLA	Wang, Shaowei,et al."Structure-activity relationship analysis of perfluoroalkyl carbonic acids on human and rat placental 3β-hydroxysteroid dehydrogenase activity.".Toxicology 480(2022):153334.