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Exp Toxicol Pathol. 2014 Mar;66(2-3):103-10. doi: 10.1016/j.etp.2013.10.002. Epub 2013 Nov 19.

Role of connexin 32 in acetaminophen toxicity in a knockout mice model.

Author information

  • 1Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd., Fukuroi, Shizuoka 437-0065, Japan. Electronic address: igarashi.isao.t6@daiichisankyo.co.jp.
  • 2Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd., Fukuroi, Shizuoka 437-0065, Japan.

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.

Copyright © 2013 Elsevier GmbH. All rights reserved.

KEYWORDS:

Acetaminophen; Connexin32; Gap junction; Intercellular communication; Liver; Mice

PMID:
24263089
[PubMed - indexed for MEDLINE]
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