title: Gap junction dysfunction reduces acetaminophen hepatotoxicity with impact on apoptotic signaling and connexin 43 protein induction in rat.
abstract: Acetaminophen (APAP) is a widely used antipyretic and analgesic agent. However, overdosing and sometimes even a recommended dose can lead to serious and conceivably fatal liver toxicity. Therefore, it is important to clarify understand mechanisms of hepatotoxicity induced by APAP. Gap junctions, formed by connexin, have important roles in maintenance of tissue homeostasis and control of cell growth and differentiation. In the liver, Cx32 is a major gap junction protein whose expression is known to gradually decrease with chronic liver disease progression. In the present study, acute hepatotoxic effects of APAP were found to be reduced in Cx32 dominant negative transgenic rats lacking normal gap junctional intercellular communication in the liver. In littermate wild-type rats, the injured centrilobular hepatocytes were positive for TUNEL staining and featured elevated expre ssion of cleaved caspase-3 and Cx43, which is not expressed in normal hepatocytes. These results suggest that APAP hepatotoxicity involves apoptosis, and induction of Cx43 expression may play an important role in the apoptotic signaling. Moreover, gap junctional functions of Cx32 can play important roles in removing damaged hepatocytes by apoptosis for liver tissue homeostasis.
authors.affiliation: Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. ayaito@-med.nagoya-cu.ac.jp
authors.forename: Aya
authors.initials: A
authors.lastname: Naiki-Ito
authors.forename: Makoto
authors.initials: M
authors.lastname: Asamoto
authors.forename: Taku
authors.initials: T
authors.lastname: Naiki
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ogawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Shinya
authors.initials: S
authors.lastname: Sato
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Shirai
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D018031:Connexin 43 / Q000187:drug effects / Q000378:metabolism*; D017630:Connexins / Q000378:metabolism; D005260:Female; D017629:Gap Junctions / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D000097002:Gap Junction beta-1 Protein
chemical_list: D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D018031:Connexin 43; D017630:Connexins; D000097002:Gap Junction beta-1 Protein