Carcinogenesis Advance Access published online on April 1, 2004
Carcinogenesis, doi:10.1093/carcin/bgh157
© 2004 by Oxford University Press
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CARCINOGENESIS
1 Department of Environmental and Molecular Medicine, Mie University School of Medicine, Mie 514-8507, Japan; Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
* Corresponding author. E-mail: kawanisi{at}doc.medic.mie-u.ac.jp.
Received 17 December 2003
; revised 16 March 2004
; accepted 22 March 2004
Chronic inflammation induced by repeated infection with Opisthorchis viverrini (OV) has been postulated to be a risk factor for cholangiocarcinoma (CHCA). To clarify the mechanism of carcinogenesis induced by repeated OV infection, we investigated the time course of 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation, inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) production and pathological features in hamsters with 2-time (2-IF) or 3-time infection (3-IF) with OV. Inflammatory cell infiltration triggered by repeated infection (3-IF > 2-IF > 1-IF) was earlier than single infection (1-IF). HPLC coupled with an electrochemical detector revealed that 8-oxodG level in the liver was the highest on day 3 in 3-IF and day 7 in 2-IF, earlier than that on day 21 in 1-IF. Notably, double immunofluorescence study revealed that formation of 8-nitroguanine and 8-oxodG appeared to increase in the epithelium of bile ducts in the order of 3-IF > 2-IF > 1-IF after the decrease of inflammatory cells. This may be explained by the results that repeated-infection increased iNOS expression in the epithelium of bile ducts in the order of 3-IF > 2-IF > 1-IF on day 90. Proliferating cell nuclear antigen was accumulated in the epithelium of bile ducts by repeated OV infection on day 90, supporting that cell proliferation was promoted via imflammationmediated DNA damage. In conclusion, more frequent OV infection can induce the expression of iNOS not only in inflammatory cells but also in the epithelium of bile ducts and subsequently causes nitrosative and oxidative damage to nucleic acid, which may participate in initiation and/or promotion steps of CHCA development.
8-oxo-7,8-dihydro-2'-deoxyguanosine, 8-nitroguanine, nitric oxide, Opisthorchis viverrini, repeated infection
Repeated infection with Opisthorchis viverrini induces accumulation of 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanine in the bile duct of hamsters via inducible nitric oxide synthase
2 Department of Anatomy, Mie University School of Medicine, Mie 514-8507, Japan
3 Department of Environmental and Molecular Medicine, Mie University School of Medicine, Mie 514-8507, Japan
4 Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
5 Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
6 Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
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