Naiki-Ito Aya, Asamoto Makoto, Naiki Taku, Ogawa Kumiko, Takahashi Satoru, Sato Shinya, Shirai Tomoyuki
Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Toxicol Pathol. 2010 Feb;38(2):280-6. doi: 10.1177/0192623309357951. Epub 2010 Jan 22.
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.
对乙酰氨基酚（APAP）是一种广泛使用的解热镇痛药。然而，过量服用甚至有时推荐剂量也可能导致严重且可能致命的肝毒性。因此，阐明APAP诱导肝毒性的机制很重要。由连接蛋白形成的间隙连接在维持组织稳态以及控制细胞生长和分化方面具有重要作用。在肝脏中，Cx32是一种主要的间隙连接蛋白，已知其表达会随着慢性肝病进展而逐渐降低。在本研究中，在肝脏中缺乏正常间隙连接细胞间通讯的Cx32显性负性转基因大鼠中，发现APAP的急性肝毒性作用有所降低。在同窝野生型大鼠中，受损的中央小叶肝细胞TUNEL染色呈阳性，且裂解的半胱天冬酶-3和Cx43表达升高，而Cx43在正常肝细胞中不表达。这些结果表明，APAP肝毒性涉及细胞凋亡，Cx43表达的诱导可能在凋亡信号传导中起重要作用。此外，Cx32的间隙连接功能在通过细胞凋亡清除受损肝细胞以维持肝组织稳态方面可能发挥重要作用。
