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High Excretion of Etheno Adducts in Liver Fluke–Infected Patients: Protection by Praziquantel against DNA Damage

Departments of ¹ Biochemistry, ² Parasitology, ³ Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; and ⁴ Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany

Requests for reprints: Helmut Bartsch, Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Phone: 49-6221-423300; Fax: 49-6221-423359. E-mail: h.bartsch{at}dkfz.de

Chronic infection by Opisthorchis viverrini (OV) is a strong risk factor for developing cholangiocarcinoma (CCA). To clarify the involvement of oxidative stress and lipid peroxidation (LPO)–derived DNA damage, the excretion of LPO-derived etheno DNA adducts was measured in urine samples collected from healthy volunteers and OV-infected Thai subjects. 1,N⁶-etheno-2'-deoxyadenosine (dA) and 3,N⁴-etheno-2'-deoxycytidine (dC) levels were quantified by immunoprecipitation/high-performance liquid chromatography/fluorescence detection and ³²P-postlabeling TLC. Excreted etheno adduct levels were related to indicators of inflammatory conditions [malondialdehyde (MDA) and nitrate/nitrite levels in urine and plasma alkaline phosphatase (ALP) activity]. Mean dA and dC levels were 3 to 4 times higher in urine of OV-infected patients; MDA, nitrate/nitrite, and ALP were also increased up to 2-fold. MDA and ALP were positively related to dA excretion. Two months after a single dose of the antiparasitic drug Praziquantel, dA and dC concentrations in urine of OV-infected subjects were decreased; MDA, nitrate/nitrite, and ALP were concomitantly lowered. We conclude that chronic OV infection through oxidative/nitrative stress leads to increased urinary excretion of the etheno-bridged deoxyribonucleosides, reflecting high LPO-derived DNA damage in vivo. These promutagenic DNA etheno adducts in bile duct epithelial cells may increase the risk of OV-infected patients to later develop CCA. Urinary dA and dC levels should be explored (a) as noninvasive risk markers for developing opisthorchiasis-related CCA and (b) as promising biomarkers to assess the efficacy of preventive and therapeutic interventions. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1658–64)