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.

中文翻译：

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暴露于1,2-二氯丙烷的小鼠肝蛋白的蛋白质组学分析。

1,2-二氯丙烷（1,2-DCP）被认为是日本胶印彩色打样工人中胆管癌的病因。本研究的目的是通过蛋白质组学分析表征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中蛋白质的差异表达，并研究了P450在介导1,2-DCP的作用中的作用。将雄性C57BL / 6JJcl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），非选择性P450抑制剂或生理盐水处理8小时/天，持续4小时周。凝胶电泳的二维差异（2D-DIGE）与基质辅助激光解吸电离飞行时间质谱（MALDI-TOF / TOF / MS）一起用于检测和鉴定受处理影响的蛋白质。对鉴定出的蛋白质进行了PANTHER过度表达测试。2D-DIGE检测到61个斑点，其强度在0和250 ppm 1,2-DCP组之间显着不同。其中，通过MALDI-TOF / TOF / MS鉴定了25个斑点。线性回归分析显示，与1-ABT共同处理的小鼠中17种蛋白质中1,2-DCP水平具有明显的趋势。1-ABT减轻了这些蛋白质的差异表达。基因本体富集分析显示与蛋白质功能相关的蛋白质过多，这些蛋白质与镍阳离子结合，羧酸酯水解酶活性和催化活性有关。