Rockey – Consulting: Ono; Grant/Research Support: Sucampo, Sucampo, Hyperion, Actelion William M. Lee – Consulting: Eli Lilly, Novartis; Grant/Research Support: Gilead, Roche, Vertex, BI, Anadys, BMS, merck; Speaking and Teaching: Merck The following people have nothing to disclose: Lafaine Grant, Jiezhun Gu, Saleh Alqahtani Background: Recently, cholangiocarcinoma cases have epidemically developed among offset color proof-printing workers check details of a printing company in Japan. In this series, DNA damage of biliary epithelial cells due to inhalation of organic solvents including 1, 2-dichloropropane and/or dichloromethane (DCM) is supposed to be associated with the carcinogenic
process. The metabolism of DCM proceeds through two pathways; a cytochrome P450 (CYP) 2E1 dependent pathway and a Thetaclass glutathione S-transferase (GST) T1-1-catalyzed pathway, where the latter has been implicated in carcinogenicity. Aim: This study was performed to examine the carcinogenic process of cholangiocarcinoma cases developing among workers of the printing company. Methods: Immunostaining of GST T1-1, CYP2E1, and gamma-H2AX was performed using formalinfixed, paraffin-embedded tissue sections of the cholangiocarcinoma cases of the printing company (n = 5). For comparison, tissue sections of cholangiocarcinoma associated with hepatolithiasis (n =16) as well as
normal livers (n =10) were used. All cholangiocarcinoma cases were surgically resected, and were histologically associated with biliary intraepithelial neoplasia click here (BilIN). Gamma-H2AX was used as a marker of DNA double strand break. Results: The immunohistochemical Lumacaftor supplier expression of GST T1-1 was observed in biliary epithelial cells of normal biliary tract and hepatocytes. The expression
of GST T1-1 was also observed in the foci of BilIN and invasive adenocarcinoma for all cholangiocarcinoma cases used. The immunohistochemical expression of CYP2E1 was observed in hepatocytes of normal livers, while normal biliary epithelial cells as well as BilIN and cholangiocarcinoma were typically negative. Gamma-H2AX was detected in foci of invasive adenocarcinoma in 4 of 5 cholangiocarcinoma cases of the printing company, and 3 cases further showed occasional expression of gamma-H2AX in non-neoplastic biliary epithelial cells as well as BilIN. In the cases of cholangiocarcinoma associated with hepatolithiasis, 7 of 16 cases showed the expression of gamma-H2AX in the invasive foci, whereas non-neoplastic biliary epithelial cells and BilIN were typically negative. Conclusions: These results suggest that the inhalation of organic solvents may act as a carcinogen for biliary epithelial cells by causing DNA damage through the GST T1-1-catalyzed pathway, and provide evidence that supports the causal relation between organic solvent inhalation and cholangiocarcinoma development in the patients.