Proteomic analysis of liver proteins of mice exposed to 1,2-dichloropropane
Proteomic analysis of liver proteins of mice exposed to 1,2-dichloropropane
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DOI：
10.1007/s00204-020-02785-4
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发表时间：
2020-05
影响因子：
6.1
通讯作者：
Xiao Zhang;Kota Morikawa;Yurie Mori;Cai Zong;Lingyi Zhang;Edwin Garner;Chinyen Huang;Wenting Wu;Jie Chang;Daichi Nagashima;T. Sakurai;S. Ichihara;S. Oikawa;G. Ichihara
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文献类型：
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作者：
Xiao Zhang;Kota Morikawa;Yurie Mori;Cai Zong;Lingyi Zhang;Edwin Garner;Chinyen Huang;Wenting Wu;Jie Chang;Daichi Nagashima;T. Sakurai;S. Ichihara;S. Oikawa;G. Ichihara
1，2-二氯丙烷（1，2-DCP）是日本胶印彩色打样工人中公认的胆管癌的致病因子。本研究的目的是通过蛋白质组学分析来表征1，2-DCP诱导的肝毒性作用的分子机制。我们定量分析了小鼠肝脏蛋白质的差异表达，并研究了P450在介导1，2-DCP作用中的作用。将雄性C57 BL/6 JJcl小鼠暴露于0、50、250或1250 ppm 1，2-DCP，并用1-氨基苯并三唑（1-ABT）（一种非选择性P450抑制剂）或盐水处理，每天8小时，持续4周。采用二维差异凝胶电泳（2D-DIGE）结合基质辅助激光解吸电离飞行时间质谱（MALDI-TOF/TOF/MS）检测和鉴定受处理影响的蛋白质。对鉴定的蛋白质进行PANTHER过度表达检验。2D-DIGE检测到61个斑点，在0和250 ppm 1，2-DCP组之间强度存在显着差异。经MALDI-TOF/TOF/MS分析，共鉴定出25个蛋白质点。线性回归分析显示，17个蛋白质点的1，2-DCP水平与1-ABT共处理小鼠的1，2-DCP水平呈显著性相关。1-ABT减轻了这些蛋白质的差异表达。基因本体富集分析表明，功能上与镍阳离子结合，羧酸酯水解酶活性和催化活性相关的蛋白质的过度表达。结果表明，暴露于1，2-DCP改变了与催化和羧酸酯水解酶活性相关的蛋白质的表达，这种影响是通过P450酶活性介导的。
1,2-Dichloropropane (1,2-DCP) is recognized as the causative agent for cholangiocarcinoma among offset color proof-printing workers in Japan. The aim of the present study was to characterize the molecular mechanisms of 1,2-DCP-induced hepatotoxic effects by proteomic analysis. We analyzed quantitatively the differential expression of proteins in the mouse liver and investigated the role of P450 in mediating the effects of 1,2-DCP. Male C57BL/6JJcl mice were exposed to 0, 50, 250, or 1250 ppm 1,2-DCP and treated with either 1-aminobenzotriazole (1-ABT), a nonselective P450 inhibitor, or saline, for 8 h/day for 4 weeks. Two-dimensional difference in gel electrophoresis (2D-DIGE) combined with matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF/TOF/MS) was used to detect and identify proteins affected by the treatment. PANTHER overrepresentation test on the identified proteins was conducted. 2D-DIGE detected 61 spots with significantly different intensity between 0 and 250 ppm 1,2-DCP groups. Among them, 25 spots were identified by MALDI-TOF/TOF/MS. Linear regression analysis showed significant trend with 1,2-DCP level in 17 proteins in mice co-treated with 1-ABT. 1-ABT mitigated the differential expression of these proteins. The gene ontology enrichment analysis showed overrepresentation of proteins functionally related to nickel cation binding, carboxylic ester hydrolase activity, and catalytic activity. The results demonstrated that exposure to 1,2-DCP altered the expression of proteins related with catalytic and carboxylic ester hydrolase activities, and that such effect was mediated by P450 enzymatic activity.