title: A trial to find appropriate animal models of dichloropropane-induced cholangiocarcinoma based on the hepatic distribution of glutathione S-transferases.
abstract: OBJECTIVE
  It has been reported that 1,2-Dichloropropane (DCP) induced cholangiocarcinoma (CCA) in offset color proof-printing workers. However, exposure to DCP by inhalation or gavage for 2 year did not induce CCA in mice and rats. The present study mapped the hepatic distribution of GST, which is known to activate dihalogenated alkanes, and proliferative and fibrotic changes in bile ducts in various species to find the most appropriate animal model of DCP-induced CCA.
  
  
  METHODS
  First, 12 each of C57BL/6J mice, Balb/cA mice, F344 rats, Syrian hamsters, and guinea pigs were divided into four equal groups and exposed to DCP at 0, 300, 1,000, or 3,000 ppm 8 hours/day for 7 days. Second, 32 Balb/cA mice and 32 Syrian hamsters were each divided into four equal groups and exposed to DCP at 0, 200, 400, and 800 ppm 6 hours/day for 14 days. After the last exposure, the animals were decapitated, and the livers were dissected out for histopathological evaluation. Immunostaining was conducted to determine the distribution of GSTT1, GSTM1, and GSTPi, as well as the expression of proliferation marker Ki67.
  
  
  RESULTS
  GSTT1, GSTM1, and GSTPi were expressed in both hepatocytes and bile duct cells in all control and exposed animals. There was no clear difference in the expression of Ki67 between the exposed groups and the control. No fibrotic changes were observed in any species or strains examined.
  
  
  CONCLUSIONS
  Expression of GSTT1 or other GST isozymes might not explain the difference in sensitivity of hepatocytes and the bile duct to DCP between humans and rodents.
authors.affiliation: Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science.
authors.forename: Lingyi
authors.initials: L
authors.lastname: Zhang
authors.forename: Cai
authors.initials: C
authors.lastname: Zong
authors.forename: Sahoko
authors.initials: S
authors.lastname: Ichihara
authors.forename: Hisao
authors.initials: H
authors.lastname: Naito
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
authors.forename: Shinji
authors.initials: S
authors.lastname: Kumagai
authors.forename: Gaku
authors.initials: G
authors.lastname: Ichihara
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000139:chemically induced*; D001653:Bile Ducts, Intrahepatic / Q000201:enzymology; D018281:Cholangiocarcinoma / Q000139:chemically induced*; D006224:Cricetinae; D004195:Disease Models, Animal; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism*; D006168:Guinea Pigs; D022781:Hepatocytes / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009784:Occupational Diseases / Q000139:chemically induced; D016273:Occupational Exposure / Q000009:adverse effects; D011327:Printing; D011407:Propane / Q000031:analogs & derivatives* / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D011407:Propane; C413545:glutathione S-transferase T1; C004765:propylene dichloride