Abstract
Recently, the International Agency for Research on Cancer issued a warning about the carcinogenicity of 1,2-dichloropropane (1,2-DCP) to humans based on an epidemiological study suggesting a relationship between the incidence of cholangiocarcinoma and occupational exposure to halogenated hydrocarbon solvent comprised mostly of 1,2-DCP. Although this dihaloalkane has been used in various industrial fields, there has been no biological evidence explaining the cholangiocarcinoma latency, as well as little understanding of general cholangiocarcinoma risk. In the present study, we explored the biliary excretion of 1,2-DCP metabolites by an untargeted metabolomics approach and the related molecular mechanism with in vitro and in vivo experiments. We hypothesized that the biliary excretion of carcinogens derived from 1,2-DCP contribute to the increased cholangiocarcinoma risk. We found that 1,2-DCP was conjugated with glutathione in the liver, and that the glutathione-conjugated forms of 1,2-DCP, including a potential carcinogen that contains a chloride atom, were excreted into bile by the bile canalicular membrane transporter, ABCC2. These results may reflect a risk in the backfiring of biliary excretion as a connatural detoxification systems for xenobiotics. Our findings would contribute to uncover the latent mechanism by which the chronic exposure to 1,2-DCP increases cholangiocarcinoma risk and future understanding of cholangiocarcinoma biology.
Highlights
In 2014, the International Agency for Research on Cancer (IARC) has re-classified 1,2-dichloropropane (DCP) into Group 1 (Carcinogenic to humans) from Group 3 (Not classifiable as to its carcinogenicity to humans)[2]
In order to test our hypothesis that 1,2-DCP and/or its metabolites are excreted into bile, we performed untargeted metabolomics and differential analyses
The dosage amount of 1,2-DCP in the present study was comparable to the estimated-intake amount of 1,2-DCP in the occupational cholangiocarcinoma cases: 4.6–31 g/day[17], which is consistent with 76–513 mg/kg/day in normal-body weight (60.4 kg) men
Summary
In 2014, the International Agency for Research on Cancer (IARC) has re-classified 1,2-dichloropropane (DCP) into Group 1 (Carcinogenic to humans) from Group 3 (Not classifiable as to its carcinogenicity to humans)[2]. The most serious problems associated with the inhalation of 1,2-DCP include the development of cholangiocarcinoma, an epithelial cell malignancy arising from the biliary-duct system[4] This cancer is classified into intrahepatic and perihilar or distal extrahepatic types according to its anatomic location. A major organ in the metabolism of various compounds, xenobiotics are generally converted to the hydrophilic form by Phase I (oxidation) and Phase II (conjugation) reactions, and are subsequently excreted into the extracellular space by the Phase III (elimination) system[9] such as ATP-binding cassette sub-family C member 2 (ABCC2) and ABCG2 These efflux transporters are located on the bile canalicular membrane of hepatocytes[10]. Our experiences addressing the physiological and clinical importance of bile canalicular transporters[14,15] and the detoxification potential of the liver[16] strongly suggested to us that the conjugated form of 1,2-DCP was likely to be excreted into bile by Phase III machinery according to the connatural detoxification system in the body
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