title: Halogenated hydrocarbon solvent-related cholangiocarcinoma risk: biliary excretion of glutathione conjugates of 1,2-dichloropropane evidenced by untargeted metabolomics analysis.
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.
authors.affiliation: Department of Pharmacy, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Toyoda
authors.affiliation: Department of Pharmacy, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Tappei
authors.initials: T
authors.lastname: Takada
authors.affiliation: Department of Pharmacy, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002273:Carcinogens / Q000378:metabolism*; D018281:Cholangiocarcinoma / Q000139:chemically induced*; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D012997:Solvents / Q000737:chemistry
chemical_list: D001647:Bile Acids and Salts; D002273:Carcinogens; D005978:Glutathione; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011407:Propane; D012997:Solvents; C000715087:ABCC2 protein, human; C004765:propylene dichloride