Ethyl pyruvate attenuates acetaminophen-induced liver injury and prevents cellular injury induced by N-acetyl-p-benzoquinone imine

Abstract

Acetaminophen, a common analgesic/antipyretic, is a frequent cause of acute liver failure in Western countries. The development of an effective cure against acetaminophen hepatotoxicity is crucial. Ethyl pyruvate, an ethyl ester derivative of pyruvic acid, has been identified as a possible candidate against acetaminophen hepatotoxicity in animal experiments. However, the mode of the hepatoprotective action of ethyl pyruvate remains unclear. We examined the hepatoprotective effect of ethyl pyruvate against hepatocyte injury and oxidative stress in a mouse model of acetaminophen hepatotoxicity. In addition, to examine whether ethyl pyruvate has direct hepatocellular protection against acetaminophen hepatotoxicity to counteract the influence of inflammatory cells, such as macrophages, we examined the effects of ethyl pyruvate on cellular injury induced by N-acetyl-p-benzoquinone imine, a toxic metabolite of acetaminophen, in a human hepatocyte cell line, HepG2 cells. Treatment with ethyl pyruvate significantly prevented increases in serum transaminase levels and hepatic centrilobular necrosis induced with an acetaminophen overdose in mice in a dose-dependent manner. Although hepatic DNA fragmentation induced by acetaminophen was also attenuated with ethyl pyruvate, nitrotyrosine formation was not inhibited. Ehyl pyruvate significantly attenuated mitochondria dehydrogenase inactivity induced by N-acetyl-p-benzoquinone imine in HepG2 cells. The attenuating effect was also observed in a rat hepatocyte cell line. Increases in annexin V and propidium iodide-stained cells induced by N-acetyl-p-benzoquinone imine were prevented with ethyl pyruvate in HepG2 cells. Pyruvic acid, a parent compound of ethyl pyruvate, tended to attenuate these changes. The results indicate that ethyl pyruvate has direct hepatocellular protection against N-acetyl-p-benzoquinone imine induced injury observed in acetaminophen overdose. The in vivo and in vitro results suggest that ethyl pyruvate attenuates acetaminophen-induced liver injury via, at least in part, its cellular protective potential.