title: Mechanisms of protection by melatonin against acetaminophen-induced liver injury in mice.
abstract: The present study was performed to determine whether melatonin protects mouse liver against severe damage induced by acetaminophen (APAP) administration and where melatonin primarily functions in the metabolic pathway of APAP to protect mouse liver against APAP-induced injury. Treatment of mice with melatonin (50 or 100 mg/kg, p.o.) 8 or 4 hr before APAP administration (750 mg/kg, p.o.) suppressed the increase in plasma alanine aminotransferase and aspartate aminotransferase activities in a dose- and a time-dependent manner. Melatonin treatment (100 mg/kg, p.o.) 4 hr before APAP administration remarkably inhibited centrilobular hepatic necrosis with inflammatory cell infiltration and increases in hepatic lipid peroxidation and myeloperoxidase activity, an index of tissue neutrophil infiltration, as well as release of nitric oxide and interleukin-6 into blood circulation at 9 hr after APAP administration. However, melatonin neither affected hepatic reduced glutathione (GSH) content nor spared hepatic GSH consumption by APAP treatment. Moreover, pretreatment with melatonin 4 hr before APAP administration did not influence the induction of hepatic heat shock protein 70 (HSP70) by APAP and melatonin alone did not induce HSP70 in mouse liver. These results indicate that exogenously administered melatonin exhibits a potent hepatoprotective effect against APAP-induced hepatic damage probably downstream of the activity of cytochrome P450 2E1, which works upstream of GSH conjugation in the pathway of APAP metabolism, via its anti-nitrosative and anti-inflammatory activities in addition to its antioxidant activity.
authors.affiliation: Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine, Yonago, Japan. tmatsura@grape.med.tottori-u.ac.jp
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Matsura
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nishida
authors.forename: Aki
authors.initials: A
authors.lastname: Togawa
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Horie
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kusumoto
authors.forename: Shuzo
authors.initials: S
authors.lastname: Ohata
authors.forename: Junya
authors.initials: J
authors.lastname: Nakada
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishibe
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamada
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Ohta
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D008099:Liver / Q000293:injuries / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008550:Melatonin / Q000502:physiology*; D051379:Mice
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D008550:Melatonin