Alpha-naphthylisothiocyanate modulates hepatobiliary transporters in sandwich-cultured rat hepatocytes

doi:10.1016/j.toxlet.2013.09.019

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	Alpha-naphthylisothiocyanate modulates hepatobiliary transporters in sandwich-cultured rat hepatocytes
	Guo, Cen 1,2; He, Lei 1; Yao, Dan 1; A, Jiye 2; Cao, Bei 2; Ren, Jin1 ; Wang, Guangji 2; Pan, Guoyu1
刊名	TOXICOLOGY LETTERS
	2014-01-03
卷号	224 期号:1 页码:93-100
关键词	Sandwich cultured hepatocytes Drug induced cholestasis Transporter Alpha-naphthylisothiocyanate
ISSN号	0378-4274
DOI	10.1016/j.toxlet.2013.09.019
文献子类	Article
英文摘要	Alpha-naphthylisothiocyanate (ANIT) induces intra-hepatic cholestasis mixed with hepatocellular injury mainly by bile ductular damage. However, its direct effect on hepatic parenchymal cells (hepatocytes) is unclear. Sandwich-cultured rat hepatocytes (SCRH) were applied to clarify this question. Though cytotoxicity was not observed (0-180 mu M) in ANIT-treated SCRH, metabonomics analysis of the hepatocytes revealed a shift in the metabolic pattern and a decrease in cellular cholesterol level, accompanied by an increase in total bile acids after 48h ANIT (5-45 mu M) treatment. To assess the function of major hepatic bile acid transporters, the accumulation and efflux of [D-Pen(2,5)]-enkephalin (DPDPE), 5 (and 6)-carboxy-2',7'-dichlorofluorescein (CDF) diacetate promoiety and deuterium-labeled sodium taurocholate (d8-TCA) were measured. ANIT incubation for either 30 min or 48 h led to dose-dependent decreases in the biliary excretion index (BEI) of DPDPE and CDF, as well as the intracellular accumulation of d8-TCA, CDF and DPDPE. The basolateral efflux of d8-TCA was also decreased with its BEI barely changed. mRNA expression of multiple uptake transporters and bile acid synthesizing enzymes was down-regulated after 48 h incubation. In conclusion, ANIT could directly induce retention of bile acids in hepatocytes by inhibiting the function of bile acid transporters, which might contribute to its cholestatic effect. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
资助项目	National Science Foundation of China[81302836] ; Hundred Talents Program of the Chinese Academy of Sciences[00000000] ; Major National Science and Technology Programs[2012ZX09301001-006] ; Major National Science and Technology Programs[2012ZX09302003]
WOS关键词	INDUCED LIVER-INJURY ; BILE-ACID TRANSPORT ; RESISTANCE-ASSOCIATED PROTEIN-3 ; NONPROTEIN SULFHYDRYL CONTENT ; STABLE OPIOID PEPTIDE ; BILIARY-EXCRETION ; IN-VITRO ; D-PENICILLAMINE(2,5) ENKEPHALIN ; OXIDATIVE STRESS ; MODEL
WOS研究方向	Toxicology
语种	英语
出版者	ELSEVIER IRELAND LTD
WOS记录号	WOS:000327887100012
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277238]
专题	药物安全性评价中心
通讯作者	Pan, Guoyu
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, Shanghai 201203, Peoples R China; 2.China Pharmaceut Univ, Key Lab Drug Metab & Pharmacokinet, Nanjing 210009, Jiangsu, Peoples R China
推荐引用方式 GB/T 7714	Guo, Cen,He, Lei,Yao, Dan,et al. Alpha-naphthylisothiocyanate modulates hepatobiliary transporters in sandwich-cultured rat hepatocytes[J]. TOXICOLOGY LETTERS,2014,224(1):93-100.
APA	Guo, Cen.,He, Lei.,Yao, Dan.,A, Jiye.,Cao, Bei.,...&Pan, Guoyu.(2014).Alpha-naphthylisothiocyanate modulates hepatobiliary transporters in sandwich-cultured rat hepatocytes.TOXICOLOGY LETTERS,224(1),93-100.
MLA	Guo, Cen,et al."Alpha-naphthylisothiocyanate modulates hepatobiliary transporters in sandwich-cultured rat hepatocytes".TOXICOLOGY LETTERS 224.1(2014):93-100.