Human and rat gonadal 3(3-hydroxysteroid dehydrogenases are suppressed by dithiocarbamate fungicides via interacting with cysteine residues

doi:10.1016/j.ecoenv.2024.116852

科研成果详情

题名	Human and rat gonadal 3(3-hydroxysteroid dehydrogenases are suppressed by dithiocarbamate fungicides via interacting with cysteine residues
作者	Zhao, Xin1,2,3,4,5,6,7,8,9; Hao, Ting1,2; Sang, Jianmin1,2; Xia, Miaomiao3,4; Li, Linxi1,2,3,4; Ge, Ren-shan1,2,3,4; Chen, Congde1,2,4,7
发表日期	2024-09-15
发表期刊	Ecotoxicology and Environmental Safety 影响因子和分区
语种	英语
原始文献类型	Article
关键词	Dithiocarbamates Steroid hormones 3(3-hydroxysteroid dehydrogenase Docking analysis Lipophilicity
其他关键词	HUMAN TYPE-1 ; ZIRAM ; STRUCTURE/FUNCTION ; INHIBITION
摘要	Dithiocarbamates have been widely used in various industrial applications, such as insecticides (ferbam) or drug (disulfiram). This study explored the inhibitory effects of dithiocarbamates on human and rat gonadal 3(3hydroxysteroid dehydrogenases (3(3-HSD) and investigated the structure-activity relationship and mechanistic insights. The inhibitory activity of six dithiocarbamates and thiourea on the conversion of pregnenolone to progesterone was evaluated using human KGN cell and rat testicular microsomes, with subsequent progesterone measurement using HPLC-MS/MS. The study found that among the tested compounds disulfiram, ferbam, and thiram exhibited significant inhibitory activity against human 3(3-HSD2 and rat 3(3-HSD1, with ferbam demonstrating the highest potency. The mode of action for these compounds was characterized, showing mixed inhibition for human 3(3-HSD2 and mixed/noncompetitive inhibition for rat 3(3-HSD1. Additionally, it was observed that dithiothreitol dose-dependently reversed the inhibitory effects of dithiocarbamates on both human and rat gonadal 3(3-HSD enzymes. The study also delved into the penetration of these dithiocarbamates through the human KGN cell membrane and their impact on progesterone production, highlighting their potency in inhibiting human 3(3-HSD2. Furthermore, bivariate correlation analysis revealed a positive correlation of LogP (lipophilicity) with IC50 values for both enzymes. Docking analysis indicated that dithiocarbamates bind to NAD+ and steroid-binding sites, with some interactions with cysteine residues. In conclusion, this study provides valuable insights into the structure-activity relationship and mechanistic aspects of dithiocarbamates as inhibitors of human and rat gonadal 3(3-HSDs, suggesting that these compounds likely exert their inhibitory effects through binding to cysteine residues.
资助项目	Zhejiang Provincial Health Department [11-CX29]; NSFC [82371610]; Zhejiang Provincial Natural Science Foundation [LY22H040010]
出版者	ACADEMIC PRESS INC ELSEVIER SCIENCE
ISSN	0147-6513
EISSN	1090-2414
卷号	283
DOI	10.1016/j.ecoenv.2024.116852
页数	10
WOS类目	Environmental Sciences ; Toxicology
WOS研究方向	Environmental Sciences & Ecology ; Toxicology
WOS记录号	WOS:001295611500001
收录类别	SCIE ; SCOPUS ; PUBMED
URL	查看原文
PubMed ID	39142049
SCOPUSEID	2-s2.0-85200944861
通讯作者地址	[Li, Linxi;Ge, Ren-shan;Chen, Congde]Wenzhou Med Univ, Yuying Childrens Hosp, Wenzhou 325027, Zhejiang, Peoples R China. ; [Li, Linxi;Ge, Ren-shan;Chen, Congde]Wenzhou Med Univ, Affiliated Hosp 2, Dept Pediat Surg, Wenzhou 325027, Zhejiang, Peoples R China.
Scopus学科分类	Pollution;Public Health, Environmental and Occupational Health;Health, Toxicology and Mutagenesis
SCOPUS_ID	SCOPUS_ID:85200944861
TOP期刊	TOP期刊
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/217482
专题	附属第二医院_小儿外科温州医科大学附属第二医院第二临床医学院，附属第二医院、育英儿童医院附属第二医院_麻醉科附属第二医院_麻醉重点学科实验室
通讯作者	Li, Linxi; Ge, Ren-shan; Chen, Congde
作者单位	1.Wenzhou Med Univ, Affiliated Hosp 2, Dept Pediat Surg, Wenzhou 325000, Zhejiang, Peoples R China; 2.Wenzhou Med Univ, Yuying Childrens Hosp, Wenzhou 325000, Zhejiang, Peoples R China; 3.Wenzhou Med Univ, Affiliated Hosp 2, Dept Anesthesiol & Perioperat Med, Wenzhou 325027, Zhejiang, Peoples R China; 4.Wenzhou Med Univ, Yuying Childrens Hosp, Wenzhou 325027, Zhejiang, Peoples R China; 5.Wenzhou Med Univ, Affiliated Hosp 2, Minist Educ, Key Lab Pediat Anesthesiol, Wenzhou 325027, Zhejiang, Peoples R China; 6.Wenzhou Med Univ, Affiliated Hosp 2, Key Lab Anesthesiol Zhejiang Prov, Wenzhou 325027, Zhejiang, Peoples R China; 7.Wenzhou Med Univ, Affiliated Hosp 2, Key Lab Children Genitourinary Dis Wenzhou, Wenzhou 325000, Zhejiang, Peoples R China; 8.Wenzhou Med Univ, Key Lab Environm & Male Reprod Med Wenzhou, Wenzhou 325000, Zhejiang, Peoples R China; 9.Wenzhou Med Univ, Affiliated Hosp 2, Key Lab Struct Malformat Children Zhejiang Prov, Wenzhou 325000, Zhejiang, Peoples R China
第一作者单位	附属第二医院_小儿外科; 第二临床医学院，附属第二医院、育英儿童医院; 附属第二医院_麻醉科; 附属第二医院; 附属第二医院_麻醉重点学科实验室; 温州医科大学
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; 附属第二医院_小儿外科
第一作者的第一单位	附属第二医院_小儿外科
推荐引用方式 GB/T 7714	Zhao, Xin,Hao, Ting,Sang, Jianmin,et al. Human and rat gonadal 3(3-hydroxysteroid dehydrogenases are suppressed by dithiocarbamate fungicides via interacting with cysteine residues[J]. Ecotoxicology and Environmental Safety,2024,283.
APA	Zhao, Xin., Hao, Ting., Sang, Jianmin., Xia, Miaomiao., Li, Linxi., ... & Chen, Congde. (2024). Human and rat gonadal 3(3-hydroxysteroid dehydrogenases are suppressed by dithiocarbamate fungicides via interacting with cysteine residues. Ecotoxicology and Environmental Safety, 283.
MLA	Zhao, Xin,et al."Human and rat gonadal 3(3-hydroxysteroid dehydrogenases are suppressed by dithiocarbamate fungicides via interacting with cysteine residues".Ecotoxicology and Environmental Safety 283(2024).