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首页> 外文期刊>Archives of Toxicology >In vitro proteomic analysis of methapyrilene toxicity in rat hepatocytes reveals effects on intermediary metabolism
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In vitro proteomic analysis of methapyrilene toxicity in rat hepatocytes reveals effects on intermediary metabolism

机译：大鼠肝细胞中甲基吡啶毒性的体外蛋白质组学分析显示出对中间代谢的影响

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摘要

The antihistaminic drug methapyrilene was withdrawn from the market in 1979 because of hepatocarcinogenicity in rats. Since then, the drug has been used as a model hepatotoxin especially for transcriptomic analyses using material from in vivo studies. Much less transcriptomics data are available from in vitro studies, and no studies have investigated proteomic effects of methapyrilene in vitro. Thus, the present study was aimed to characterize the proteomic response of primary rat hepatocytes to methapyrilene, to broaden our knowledge on the molecular mechanisms of methapyrilene toxicity, and to compare the results of collagen sandwich-cultured hepatocytes to in vivo data. In vitro methapyrilene concentrations (0.39 mu M, 6.25 mu M, and 100 mu M) were chosen to cover an in vivo-relevant range. Based on published pharmacokinetic data they correspond to concentrations in portal vein blood for previously in vivo-tested doses of methapyrilene, up to a concentration showing slight cytotoxicity. Analysis of proteomic alterations by two-dimensional gel electrophoresis and mass-spectrometric protein identification demonstrated consistent and concentration-dependent effects of methapyrilene, in particular on mitochondrial proteins. Data suggest substantial deregulation of amino acid and ammonia metabolism and effects on mitochondrial energy supply pathways. The effects identified in vitro concur well with into previous in vivo observations. Several effects, for example, the influence of methapyrilene on S-adenosylmethionine metabolism, have not been described previously. The data suggest that already non-toxic concentrations of methapyrilene alter components of the intermediary metabolism, such as branched-chain amino acid metabolism, as well as urea and tricarboxylic cycle enzymes. In summary, data substantially add to our knowledge on molecular mechanisms of methapyrilene hepatotoxicity at the protein level.
机译：由于大鼠肝癌发生性，1979年从市场中取出了抗组胺药药物甲太烷。从那时起，药物已被用作肝毒素的模型，特别是用于通过体内研究使用材料的转录组分析。在体外研究中可以获得更少的转录组织数据，并且没有研究体外甲太烯的蛋白质组学作用。因此，本研究旨在表征原代大鼠肝细胞对甲基吡啶的蛋白质组学反应，以扩大我们对甲甲烷基苯毒性的分子机制的知识，并将胶原型夹心培养的肝细胞的结果与体内数据进行比较。选择体外甲基吡啶浓度（0.39μm，6.25μm和100μm）以覆盖体内相关的范围。基于已发表的药代动力学数据，它们对应于预先在体内甲基吡啶的体内甲基吡啶的门静脉血液中的浓度，直至显示出浓度的浓度，显示出轻微的细胞毒性。通过二维凝胶电泳和质谱蛋白质鉴定的蛋白质组学改变分析，表明了甲烷基脲，特别是对线粒体蛋白质的一致和浓度依赖性作用。数据表明氨基酸和氨代谢的大量放松管制和对线粒体能量供应途径的影响。在体外鉴定的效果在体内观察中进行良好。例如，尚未描述若干效果，例如，甲炔烯酮对S-腺苷甲基硫甲硫醚代谢的影响。该数据表明，已经有毒浓度的甲烷基芳基改变中间代谢的组分，例如支链氨基酸代谢，以及尿素和三羧酸循环酶。总之，数据基本上增加了我们关于蛋白质水平甲烷基乙烯肝毒性的分子机制的知识。

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