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Oxidative Medicine and Cellular Longevity
Volume 2017 (2017), Article ID 9736836, 9 pages
https://doi.org/10.1155/2017/9736836
Research Article

Spontaneous Production of Glutathione-Conjugated Forms of 1,2-Dichloropropane: Comparative Study on Metabolic Activation Processes of Dihaloalkanes Associated with Occupational Cholangiocarcinoma

Department of Pharmacy, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

Correspondence should be addressed to Tappei Takada

Received 11 January 2017; Revised 17 March 2017; Accepted 20 March 2017; Published 7 May 2017

Academic Editor: Guo-Fang Zhang

Copyright © 2017 Yu Toyoda et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Recently, epidemiological studies revealed a positive relationship between an outbreak of occupational cholangiocarcinoma and exposure to organic solvents containing 1,2-dichloropropane (1,2-DCP). In 1,2-DCP-administered animal models, we previously found biliary excretion of potentially oncogenic metabolites consisting of glutathione- (GSH-) conjugated forms of 1,2-DCP (GS-DCPs); however, the GS-DCP production pathway remains unknown. To enhance the understanding of 1,2-DCP-related risks to human health, we examined the reactivity of GSH with 1,2-DCP in vitro and compared it to that with dichloromethane (DCM), the other putative substance responsible for occupational cholangiocarcinoma. Our results showed that 1,2-DCP was spontaneously conjugated with GSH, whereas this spontaneous reaction was hardly detected between DCM and GSH. Further analysis revealed that glutathione S-transferase theta 1 (GSTT1) exhibited less effect on the 1,2-DCP reaction as compared with that observed for DCM. Although GSTT1-mediated bioactivation of dihaloalkanes could be a plausible explanation for the production of reactive metabolites related to carcinogenesis based on previous studies, this catalytic pathway might not mainly contribute to 1,2-DCP-related occupational cholangiocarcinoma. Considering the higher catalytic activity of GSTT1 on DCM as compared with that on 1,2-DCP, our findings suggested differences in the activation processes associated with 1,2-DCP and DCM metabolism.