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Abstract:
Pyrrolizidine alkaloids (PAs) are widely occurring phytotoxins which can induce severe liver damage in humans and other mammalian species by mechanisms that are not fully understood. Therefore, we investigated the development of PA hepatotoxicity in vivo, using an acutely toxic dose of the PA senecionine in mice, in combination with intravital two-photon microscopy, histology, clinical chemistry, and in vitro experiments with primary mouse hepatocytes and liver sinusoidal endothelial cells (LSECs). We observed pericentral LSEC necrosis together with elevated sinusoidal marker proteins in the serum of senecionine-treated mice and increased sinusoidal platelet aggregation in the damaged tissue regions. In vitro experiments showed no cytotoxicity to freshly isolated LSECs up to 500 µM senecionine. However, metabolic activation of senecionine by preincubation with primary mouse hepatocytes increased the cytotoxicity to cultivated LSECs with an EC_50 of approximately 22 µM. The cytochrome P450 (CYP)-dependency of senecionine bioactivation was confirmed in CYP reductase-deficient mice where no PA-induced hepatotoxicity was observed. Therefore, toxic metabolites of senecionine are generated by hepatic CYPs, and may be partially released from hepatocytes leading to destruction of LSECs in the pericentral region of the liver lobules. Analysis of hepatic bile salt transport by intravital two-photon imaging revealed a delayed uptake of a fluorescent bile salt analogue from the hepatic sinusoids into hepatocytes and delayed elimination. This was accompanied by transcriptional deregulation of hepatic bile salt transporters like Abcb11 or Abcc1 . In conclusion, senecionine destroys LSECs although the toxic metabolite is formed in a CYP-dependent manner in the adjacent pericentral hepatocytes.
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最新影响因子:6.168 | 期刊ISSN:0340-5761 | CiteScore:4.79 |
出版周期:Monthly | 是否OA:YES | 出版年份:1974 |
自引率:8.50% | 研究方向:医学-毒理学 |
出版地区:GERMANY |
SCI期刊coverage:Science Citation Index Expanded(科学引文索引扩展)
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Official journal of EUROTOX Edited on behalf of the Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie The provision of up-to-date information on the latest advances in toxicology is one of the main services that Archives of Toxicology offers its readers. Particular emphasis is laid on studies relating to defined effects of chemicals and mechanisms of toxicity including toxic activities at the molecular level in humans and experimental animals. Space is also devoted to new insights into analysis and toxicokinetics and to forensic toxicology. Review articles of general interest to toxicologists are a further important feature of the journal. Experimental and clinical data relating to toxicology can be submitted for publication in Archives of Toxicology as Original investigations Review articles Short communications or Letters to the editors
《欧洲毒理学》官方期刊是代表德国格列斯沙夫毛皮实验与毒理学研究所编辑的,提供毒理学最新进展的最新信息是毒理学档案为读者提供的主要服务之一。特别强调的是关于化学物质的明确影响和毒性机制的研究,包括在人类和实验动物分子一级的毒性活动。空间也致力于分析和毒物动力学和法医毒理学的新见解。毒理学家普遍感兴趣的综述文章是该杂志的另一个重要特征。与毒理学有关的实验和临床数据可作为原始调查综述文章提交毒理学档案,或作为简短的通信或信件发送给编辑
大类(学科) | 小类(学科) | 学科排名 |
医学 |
TOXICOLOGY (毒理学) 2区 |
7/94 |
年度总发文量 | 年度论文发表量 | 年度综述发表量 |
257 | 212 | 45 |
引文计数(2018)
文献(2015-2017)
3002次引用
627篇文献
序号 | 类别 | 排名 | 百分位 |
1 |
大类(学科):Pharmacology, Toxicology and Pharmaceutics
小类(学科):Toxicology
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#9/111
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2 |
大类(学科):Environmental Science
小类(学科):Health, Toxicology and Mutagenesis
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#11/107
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研究方向:毒理
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研究方向:毒理
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研究方向:化学科学 环境化学 化学环境污染与健康
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研究方向:医药科学 预防医学 卫生毒理
审稿时间: 2个月内
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研究方向:毒理
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研究方向:毒理
影响因子:1.992
ISSN:1976-1457
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影响因子:1
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影响因子:9.298
ISSN:1930-7381
研究方向:医学-内分泌学与代谢
影响因子:4.807
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影响因子:4.725
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研究方向:ENDOCRINOLOGY & METABOLISM-NUTRITION & DIETETICS
影响因子:1.417
ISSN:1575-0922
研究方向:-
影响因子:5.551
ISSN:0307-0565
研究方向:医学-内分泌学与代谢
影响因子:0.704
ISSN:0985-0562
研究方向:医学-内分泌学与代谢
发表一篇学和医学成像类SCI论文
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