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.
Keywords: 1,2-Dichloropropane; Cholangiocarcinoma; Hepatotoxicity; P450; Proteomics.