Melatonin protects on toxicity by acetaminophen but not on pharmacological effects in mice.
The pineal gland and its main hormone, melatonin (MLT), are involved in a variety of physiological processes. MLT is a member of the indolamine family and has significant antioxidative activity. Acetaminophen (AA) is the most widely used medication in the world, both by prescription and over the counter. In large doses, AA is hepatotoxic causing oxidative stress and lipid peroxidation. Therefore, antioxidants have been used to protect against the toxicity of AA. Here, we examined in vitro and in vivo the protective effects of MLT against AA-induced toxicity in mice. MLT (100 microM) had a significant protective effect on the AA (7 mM)-induced loss of cell viability in mouse primary cultured hepatocytes as determined using the 3H-thymidine incorporation assay and MTT assay. The AA-induced generation of reactive oxygen species (ROS) peaked at 6 h and was followed by an increase in lipid peroxidation at 12 h in hepatocytes. MLT (0.1, 1, 10 or 100 microM) dose-dependently attenuated the increase in both production of ROS and lipid peroxidation by AA. Similarly, in vivo, AA (400, 600 or 800 mg/kg, intraperitoneally)-induced mortality and hepatotoxicity were significantly decreased by MLT (10 mg/kg, subcutaneously). Pretreatment with MLT had a greater protective effect on the hepatotoxicity of AA than post-treatment. However, MLT had no protective effect on the antipyretic effect or antinociception caused by AA. These results suggest that MLT is potentially useful for preventing AA-induced toxicity, but not the antipyretic effect or antinociception caused by AA.
Kanno
Syu-ichi
S
Department of Pharmacology and Toxicology, Cancer Research Institute, Tohoku Pharmaceutical University, Sendai, Japan. syu-kan@tohoku-pharm.ac.jp
Tomizawa
Ayako
A
Hiura
Takako
T
Osanai
Yuu
Y
Kakuta
Mai
M
Kitajima
Yasue
Y
Koiwai
Kimiko
K
Ohtake
Takaharu
T
Ujibe
Mayuko
M
Ishikawa
Masaaki
M
D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control; D022781:Hepatocytes / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010147:Pain Measurement / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D000975:Antioxidants; D017382:Reactive Oxygen Species; D000082:Acetaminophen; D008550:Melatonin; D013936:Thymidine