ABSTRACT: Protective effects of carnosine or histidine against acetaminophen-induced hepatotoxicity in Balb/cA mice were examined. Each compound, at 0.5, 1, or 2 g/L, was added into the drinking water for 4 wk. Acute liver injury was induced by acetaminophen treatment intraperitoneally (i.p. 350 mg/kg body weight). Acetaminophen treatment significantly depleted hepatic GSH and ascorbic acid levels, increased hepatic level of malonyldialdehyde (MDA), reactive oxygen species (ROS), and oxidized glutathione (GSSG), as well as decreased hepatic activity of glutathione peroxidase (GPX), catalase, and superoxide dismutase (SOD) (P < 0.05). However, the pre-intake of carnosine or histidine significantly alleviated acetaminophen-induced oxidative stress by increasing GSH content, decreasing MDA, ROS, and GSSG formations, and retaining activity of GPX, catalase, and SOD in liver (P < 0.05). The pre-intake of these compounds also significantly retarded subsequent acetaminophen-induced increase of cytochrome P450 2E1 activity (P < 0.05). Acetaminophen treatment increased the hepatic levels of interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-alpha, and monocyte chemoattractant protein (MCP)-1 (P < 0.05). The pre-intake of carnosine or histidine significantly diminished acetaminophen-induced elevation of these cytokines (P < 0.05). The impact of these compounds on mRNA expression of GPX, TNF-alpha, and MCP-1 indicated that these compounds could act at a transcription level. These results support that carnosine and histidine are potent hepatoprotective agents.