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.

Protection of a Ceramide Synthase 2 Null Mouse from Drug-induced Liver Injury

“…Gap junction channels consist of Cx proteins and are involved in intercellular communication and in the amplification of liver inflammation and injury (1,39,41,43). Ablation of Cx32, a major Cx in liver, abrogates liver injury induced by the same four hepatotoxic agents used in this study (1, 39 -41), and APAP-induced-Cx43 expression was inhibited in Cx32 dominant-negative transgenic rats (41) similar to that observed in the CerS2 null mouse.…”

Modifications in Connexin Expression in Liver Development and Cancer

“…In this context, hepatocytes of rats that have been administered acetaminophen display high levels of Cx43. In this model, Cx43 colocalised with caspase 3 in the liver parenchymal cells, suggesting its involvement in acetaminophen-induced hepatocellular apoptosis (Naiki-Ito et al, 2010). This is further supported by the notion that hepatocyte damage and apoptosis are much less manifested in Cx43-defi cient mice that received carbon tetrachloride compared with wild-type animals (Cogliati et al, 2011).…”

Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice

“…Nonetheless, hepatic connexin expression patterns undergo drastic changes upon chronic liver disease, such as in liver fibrosis and cirrhosis as well as during acute liver injury (Maes et al, 2015b; Vinken, 2012). In this respect, our and other groups previously reported a switch in RNA and protein production from Cx32 and Cx26 to Cx43 upon APAP intoxication in rodents (Maes et al, 2016a; Naiki-Ito et al, 2010). This upregulation of Cx43 is due to recruitment of Cx43-expressing inflammatory cells, but equally reflects de novo production of Cx43 by hepatocytes (Maes et al, 2016a).…”