Gap junction dysfunction reduces acetaminophen hepatotoxicity with impact on apoptotic signaling and connexin 43 protein induction in rat.
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.
Naiki-Ito
Aya
A
Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. ayaito@-med.nagoya-cu.ac.jp
Asamoto
Makoto
M
Naiki
Taku
T
Ogawa
Kumiko
K
Takahashi
Satoru
S
Sato
Shinya
S
Shirai
Tomoyuki
T
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
D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D018031:Connexin 43; D017630:Connexins; D000097002:Gap Junction beta-1 Protein