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Adaptive homeostasis of the vitamin D–vitamin D nuclear receptor axis in 8-methoxypsoralen-induced hepatotoxicity

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成果类型:
期刊论文
作者:
Zhao, Guolin;Elhafiz, Muhanad;Jiang, Jingwei;Das, Debanjan;Li, Zhijian;Zhou, Wang;Fan, Sisi;Wang, Changling;Yuan, Ziqiao;Xu, Dengqiu;Jiang, Zhenzhou;Zhang, Luyong*;Wang, Tao*
通讯作者:
Zhang, Luyong;Wang, Tao
作者机构:
[Das, Debanjan; Zhao, Guolin; Wang, Changling; Xu, Dengqiu; Fan, Sisi; Jiang, Jingwei; Elhafiz, Muhanad; Wang, Tao; Zhou, Wang; Zhang, Luyong; Jiang, Zhenzhou; Li, Zhijian; Yuan, Ziqiao] China Pharmaceut Univ, Jiangsu Key Lab Drug Screening, 24 Tong Jia Xiang, Nanjing 210009, Jiangsu, Peoples R China.
[Wang, Tao; Zhang, Luyong] China Pharmaceut Univ, Jiangsu Ctr Pharmacodynam Res & Evaluat, Nanjing 210009, Jiangsu, Peoples R China.
[Zhang, Luyong] Guangdong Pharmaceut Univ, Ctr Drug Screening & Pharmacodynam Evaluat, Sch Pharm, Guangzhou 510006, Guangdong, Peoples R China.
[Zhang, Luyong] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China.
[Jiang, Zhenzhou] China Pharmaceut Univ, Key Lab Drug Qual Control & Pharmacovigilance, Nanjing 210009, Jiangsu, Peoples R China.
通讯机构:
[Zhang, Luyong; Wang, Tao] China Pharmaceut Univ, Jiangsu Key Lab Drug Screening, 24 Tong Jia Xiang, Nanjing 210009, Jiangsu, Peoples R China.
语种:
英文
关键词:
8-MOP;8-methoxypsoralen;PUVA;8-methoxypsoralen with ultraviolet A radiation (UVA) therapy;VD;vitamin D;VDR;vitamin D receptor;MDR3;multidrug resistance 3 P-glycoprotein;25(OH)D;25-hydroxy vitamin D;γ-GGT;γ-glutamyl transpeptidase;TBIL;total bilirubin;ALT;alanine aminotransferase;LCA;lithocholic acid;Calp;calcipotriol hydrate;VDD;vitamin D-deficient;CLD;conventional lighting and diet;SD;Sprague-Dawley;TBA;total bile acids;ECL;Elecsys electrochemiluminescence;HEK;Human embryonic kidney;Veh;vehicle;hVDR LBD;human VDR ligand-binding domain;ANOVA;one-way analysis of variance;2MV;1,25-dihydroxy vitamin D analog;MTD;maximum tolerant dose;CYP7A1;cholesterol 7 alpha-hydroxylase;MRP3;multidrug resistance-associated protein 3;FXR;farnesoid X receptor;SHP;small heterodimer partner;NR;nuclear receptor;DBD;DNA-binding domain;LBD;ligand-binding domain;8-MOP;Liver injury;Vitamin D;Vitamin D nuclear receptor
期刊:
TOXICOLOGY AND APPLIED PHARMACOLOGY
ISSN:
0041-008X
年:
2019
卷:
362
页码:
150-158
文献类别:
WOS:Article
所属学科:
WOS学科类别:Pharmacology & Pharmacy;Toxicology
入藏号:
基金类别:
National Natural Science Foundation of China, China [81320108029, 81773995]; National "Major Scientific and Technological Special Project for Significant New Drugs Creation" Project, China [2015ZX09501004-002-004]; Specific Fund for Public Interest Research of Traditional Chinese Medicine, Ministry of Finance, China [201507004-002]; Key Development Projects of Xinjiang Uyghur Autonomous Region, China [2016B03044-3]; National Major New Drug Initiative Science and Technology Project "National Medicine New Variety Research and Development and Key Innovation Technology" subtopic, China [2017ZX09301060-005]; 111 Project, China [111-2-07]
机构署名:
本校为其他机构
院系归属:
药学院
摘要:
8-methoxypsoralen (8-MOP) with ultraviolet A radiation therapy (PUVA) is the standard therapy for patients with psoriasis, despite the reported potential risks of 8-MOP-induced cholestatic liver injury in both humans and animals. Usually, patients with chronic cholestasis exhibit lower serum 25-hydroxy vitamin D (25(OH)D) levels. But those patients receiving PUVA for psoriasis showed an increase in serum 25(OH)D levels, probably highlighting that the vitamin D vitamin D nuclear receptor (VD-VDR) axis play a protective role in 8-MOP-induced hepatotoxicity. The present study confirmed 8-MOP could increase serum 25(OH)D levels in conventional lighting and diet (CLD) and vitamin D deficient (VDD) Sprague-Dawley rats. Potential liver risks were also found in CLD and VDD rats after 8-MOP treatment. We proved that 8-MOP could be a potent ligand for VDR using molecular docking and luciferase report assay. Effect of 8-MOP on VDR subcellular distribution was determined using human liver cell line L02. We found 8-MOP could increase VDR protein expression in the nuclear and cytosol extracts and also total cell extracts in L02. siRNAs for VDR were used to determine the role of VDR in protecting 8-MOP-induced cholestasis and potential cellular mechanisms. The results showed 8-MOP could affect the CYP7A1, SHP and MRP3 expression via VDR, and such effects could be reversed by knockdown of VDR expression, suggesting a vital role of VDR involved in 8-MOP-regulated bile acid synthesis and transportation. In conclusion, these results revealed activation of VD VDR axis may play a beneficial role in 8-MOP-mediated regulation of bile acid synthesis and transportation.
参考文献:
Antony P, 2010, J MED CHEM, V53, P1159, DOI 10.1021/jm9014636
Belorusova AY, 2014, J MED CHEM, V57, P4710, DOI 10.1021/jm5002524
BENGOA JM, 1984, HEPATOLOGY, V4, P261, DOI 10.1002/hep.1840040215
BJELLERUP M, 1979, ACTA DERM-VENEREOL, V59, P371
BOLT MJG, 1981, HEPATOLOGY, V1, P436

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