Protective effect of melatonin against Opisthorchis viverrini-induced oxidative and nitrosative DNA damage and liver injury in hamsters.
The liver fluke, Opisthorchis viverrini, is the risk factor of cholangiocarcinoma, which is a major health problem in northeastern Thailand. Production of reactive oxygen and nitrogen species during the host's response leads to oxidative and nitrosative stress contributing to carcinogenesis. We investigated the protective effect of melatonin against O. viverrini-induced oxidative and nitrosative stress and liver injury. Hamsters were infected with O. viverrini followed by oral administration of various doses of melatonin (5, 10, and 20 mg/kg body weight) for 30 days. Uninfected hamsters served as controls. Compared to the levels in O. viverrini-infected hamsters without melatonin treatment, the indoleamine decreased the formation of oxidative and nitrosative DNA lesions, 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-nitroguanine, in the nucleus of bile duct epithelium and inflammatory cells, in parallel with a reduction in 3-nitrotyrosine. Melatonin also reduced the expression of heme oxygenase-1 and cytokeratin 19, nitrate/nitrite levels, and bile duct proliferation in the liver. Alanine transaminase activity and the levels of 8-isoprostane and vitamin E were also dose dependently decreased in the plasma of melatonin-treated hamsters. Melatonin reduced the mRNA expression of oxidant-generating genes [inducible nitric oxide synthase, nuclear factor-kappa B (NF-κB), and cyclooxygenase-2] and proinflammatory cytokines (TNF-α and IL-1β), accompanied by an increase in the expression of antioxidant genes [nuclear erythroid 2-related factor 2 (Nrf2) and manganese superoxide dismutase]. Thus, melatonin may be an effective chemopreventive agent against O. viverrini-induced cholangiocarcinoma by reducing oxidative and nitrosative DNA damage via induction of Nrf2 and inhibition of NF-κB-mediated pathways.
Laothong
Umawadee
U
Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
Pinlaor
Porntip
P
Hiraku
Yusuke
Y
Boonsiri
Patcharee
P
Prakobwong
Suksanti
S
Khoontawad
Jarinya
J
Pinlaor
Somchai
S
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D001652:Bile Ducts / Q000187:drug effects; D006224:Cricetinae; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000469:parasitology; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009889:Opisthorchiasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009891:Opisthorchis / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects*; D013312:Stress, Physiological / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood
D000975:Antioxidants; D016207:Cytokines; D051267:NF-E2-Related Factor 2; D014409:Tumor Necrosis Factor-alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D051547:Heme Oxygenase-1; D008550:Melatonin