A Protective Role for Metallothionein in Acetaminophen-caused Liver Toxicity via Oxidative Stress

Baoxu Zhang^a,b Masahiko Satoh^a and Chiharu Tohyama^a

^aEnvironmental Health Sciences Division, National Institute for Environmental Studies, Tsukuba 305-0053, Japan and ^bDepartment of Toxicology, Beijing Medical University, Beijing 100083, China

To investigate the possible involvement of metallothionein (MT) in acetaminophen (AC)-induced liver damage, MT-I and MT-II gene knock-out transgenic mice (MT-null mice) and wild-type control mice were i.p. treated with AC at a single dose of 250 mg/kg and compared. At 24 h after AC treatment severe liver damage characterized by necrosis of hepatocytes and increased serum GPT activity was found in MT-null mice while a limited degree of change such as a slight increase in serum GPT activity without necrosis was observed in wild-type mouse liver. MT-null hepatocytes also showed elevated PCNA (proliferating cell nuclear antigen)-positive activity around the necrosis area. AC administration resulted in an increase in lipid peroxidation in MT-null mice, but not in the wild-type mice. The liver in the wild-type mice showed an increased MT amount after AC treatment. These results indicate that MT acts as an endogenous defensive factor against AC-induced hepatotoxicity via oxidative stress.