title: Role of connexin 32 in acetaminophen toxicity in a knockout mice model.
abstract: Gap junctional intercellular communication (GJIC), by which glutathione (GSH) and inorganic ions are transmitted to neighboring cells, is recognized as being largely involved in toxic processes of chemicals. We examined acetaminophen (APAP)-induced hepatotoxicity clinicopathologically using male wild-type mice and mice lacking the gene for connexin32, a major gap junction protein in the liver [knockout (Cx32KO) mice]. When APAP was intraperitoneally administered at doses of 100, 200, or 300mg/kg, hepatic centrilobular necrosis with elevated plasma aminotransferase activities was observed in wild-type mice receiving 300mg/kg, and in Cx32KO mice given 100mg/kg or more. At 200mg/kg or more, hepatic GSH and GSSG contents decreased significantly and the effect was more severe in wild-type mice than in Cx32KO mice. On the other hand, markedly decreased GSH staining was observed in the hepatic centrilobular zones of Cx32KO mice compared to that of wild-type mice. These results demonstrate that Cx32KO mice are more susceptible to APAP hepatotoxicity than wild-type mice, and indicate that the distribution of GSH of the centrilobular zones in the hepatic lobules, rather than GSH and GSSG contents in the liver, is important in APAP hepatotoxicity. In conclusion, Cx32 protects against APAP-induced hepatic centrilobular necrosis in mice, which may be through the GSH transmission to neighboring hepatocytes by GJIC.
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd., Fukuroi, Shizuoka 437-0065, Japan. Electronic address: igarashi.isao.t6@daiichisankyo.co.jp.
authors.forename: Isao
authors.initials: I
authors.lastname: Igarashi
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd., Fukuroi, Shizuoka 437-0065, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Maejima
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd., Fukuroi, Shizuoka 437-0065, Japan.
authors.forename: Kiyonori
authors.initials: K
authors.lastname: Kai
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd., Fukuroi, Shizuoka 437-0065, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Arakawa
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd., Fukuroi, Shizuoka 437-0065, Japan.
authors.forename: Munehiro
authors.initials: M
authors.lastname: Teranishi
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd., Fukuroi, Shizuoka 437-0065, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbuissho
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D017630:Connexins / Q000235:genetics / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D000097002:Gap Junction beta-1 Protein
chemical_list: D000082:Acetaminophen; D017630:Connexins; D005978:Glutathione; D019803:Glutathione Disulfide; D000097002:Gap Junction beta-1 Protein
keywords: Acetaminophen; Connexin32; Gap junction; Intercellular communication; Liver; Mice