Melatonin downregulates nuclear erythroid 2-related factor 2 and nuclear factor-kappaB during prevention of oxidative liver injury in a dimethylnitrosamine model.
Melatonin has potent hepatoprotective effects as an antioxidant. However, the signaling pathway of melatonin in the induction of antioxidant enzymes against acute liver injury is not fully understood. The study aimed to determine whether melatonin could prevent dimethylnitrosamine (DMN)-induced liver injury through nuclear erythroid 2-related factor 2 (Nrf2) and inflammation. Liver injury was induced in rats by a single injection of DMN (30 mg/kg, i.p.). Melatonin treatment (50 mg/kg/daily, i.p.) was initiated 24 hr after DMN injection for 14 days, after which the rats were killed and samples were collected. Serum and antioxidant enzyme activities improved in melatonin-treated rats, compared with DMN-induced liver injury group (P < 0.01). Melatonin reduced the infiltration of inflammatory cells and necrosis in the liver, and increased the expression of NADPH: quinone oxidoreductase-1, heme oxygenase-1, and superoxide dismutase-2, which were decreased by DMN. Melatonin increased expression of novel transcription factor, Nrf2, and decreased expression of inflammatory mediators including tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and inducible nitric oxide synthase. The increased nuclear binding of nuclear factor-kappa B (NF-kappaB) in the DMN-induced liver injury group was inhibited by melatonin. Our results show that melatonin increases antioxidant enzymes and Nrf2 expression in parallel with the decrease of inflammatory mediators in DMN-induced liver injury, suggesting that melatonin may play a role of antioxidant defense via the Nrf2 pathway, by reducing inflammation by NF-kappaB inhibition.
Jung
Kyung Hee
KH
Clinical Research Center.
Hong
Sang-Won
SW
Clinical Research Center.
Zheng
Hong-Mei
HM
Clinical Research Center.
Lee
Don-Haeng
DH
Department of Internal Medicine, College of Medicine, Inha University, Incheon, Korea.
Hong
Soon-Sun
SS
Clinical Research Center.
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D004128:Dimethylnitrosamine; D015536:Down-Regulation / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000293:injuries / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D004128:Dimethylnitrosamine; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D051547:Heme Oxygenase-1; D007527:Isoenzymes; D008315:Malondialdehyde; D008550:Melatonin; D016660:NAD(P)H Dehydrogenase (Quinone); D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D012333:RNA, Messenger; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C495637:Nfe2l2 protein, rat; C507703:NQO1 protein, rat; C119995:glutathione S-transferase alpha