Connexin 32 dominant-negative mutant transgenic rats are resistant to hepatic damage by chemicals

Authors

  • Makoto Asamoto,

    1. Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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  • Naomi Hokaiwado,

    Corresponding author
    1. Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
    • Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 Japan
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    • fax: 81-51-842-0817

  • Toshiya Murasaki,

    1. Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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  • Tomoyuki Shirai

    1. Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Abstract

Connexins are subunits of gap junction channels, which allow direct transfer of ions, secondary messenger molecules, and other metabolites between contacting cells. Gap junctions are believed to be involved in tissue homeostasis, embryonic development, and control of cell proliferation. Several studies have shown that cell damage signals are transmitted through gap junctions when cells are irradiated or when cells bearing the herpes simplex virus-thymidine kinase (HSV-TK) gene are treated with ganciclovir. We established 2 lines of transgenic rats with a dominant-negative mutant of connexin 32 gene under control of the albumin promoter. In the livers of transgenic rats, membrane localization of normal endogenous connexin 32 protein is disturbed, and gap junction capacity measured by scrape dye-transfer assay in vivo is markedly decreased when compared with wild-type rats. The present investigation concerned susceptibility to the liver-toxic substances D-galactosamine and carbon tetrachloride. These toxicants induced massive liver cell death and elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the wild-type rats; however, much fewer liver cells were damaged and serum enzyme elevation was much lower in the transgenic rats. In conclusion, gap junctional intercellular communication (GJIC) plays an important role in toxic effects of chemicals; damage or death signals may pass through gap junctions in the rat liver in vivo. (HEPATOLOGY 2004;40:205–210.)

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