Urinary 8-Oxo-7,8-Dihydro-2′-Deoxyguanosine in Patients with Parasite Infection and Effect of Antiparasitic Drug in Relation to Cholangiocarcinogenesis

Abstract

Parasite infection of Opisthorchis viverrini is a major risk factor for cholangiocarcinoma. Our previous immunohistochemical studies showed that O. viverrini infection induced oxidative DNA lesions in the bile duct epithelium during cholangiocarcinoma development. The current study assessed the levels of 8-oxo-7,8-dihydro-2 ¶-deoxyguanosine (8-oxodG), an oxidative DNA lesion, in the urine and leukocytes of O. viverrini -infected subjects and cholangiocarcinoma patients. Forty-nine O. viverrini -infected patients, 55 cholangiocarcinoma patients, and 17 healthy controls were enrolled in the study. We measured 8-oxodG levels in the urine and leukocytes of these subjects using an electrochemical detector coupled to high-performance liquid chromatography. O. viverrini -infected patients were assessed before treatment and 2 months and 1 year after praziquantel treatment. Urinary 8-oxodG levels were significantly higher in cholangiocarcinoma patients (6.83 F 1.00 Mg/g creatinine) than in O. viverrini -infected patients (4.45 F 0.25 Mg/g creatinine; P < 0.05) and healthy subjects (3.03 F 0.24 Mg/g creatinine; P < 0.01) and higher in O. viverrini -infected subjects than in healthy subjects (P < 0.01). The urinary 8-oxodG levels in O. viverrini -infected patients significantly decreased 2 months after praziquantel treatment and were comparable with levels in healthy subjects 1 year after treatment. Urinary 8-oxodG levels were significantly correlated with leukocyte 8-oxodG levels, plasma nitrate/nitrite levels, and aspartate aminotransferase activity. In conclusion, this study, in addition to our previous studies, indicates that 8-oxodG formation by parasite infection may play an important role in cholangiocarcinoma development. Urinary 8-oxodG may be a useful biomarker to monitor not only infection but also carcinogenesis. (Cancer Epidemiol Biomarkers Prev 2008;17(3):518 -24)

Human liver flukes

“…Upregulation of inducible nitric oxide synthase (iNOS) and subsequent oxidative/nitritative DNA damage has been demonstrated in Opisthorchis viverrini-related cholangiocarcinoma in humans (54) , and in Clonorchis sinensis infected mice (49,55) . Oxidative/nitritative damage to proteins via reactive oxygen species may prolong the oxidative stress (37) .…”

Association of CYP39A1, RUNX2 and Oxidized Alpha-1 Antitrypsin Expression in Relation to Cholangiocarcinoma Progression

“…Diverse exposure to risk factors for CCA result in varying geographic incidences with parasitic infections, such as liver fluke, Opisthorchis viverrini (O. viverrini), chronic viral hepatitis and cirrhosis including hepatitis C virus (HCV), hepatitis B virus (HBV), liver cirrhosis, and hepatolithiasis (Shin et al, 2010). A major mechanism linking between inflammation and CCA is related to the generation of free radicals such as superoxide anion (O2¯•), nitric oxide (NO) and other reactive oxygen (ROS) * and nitrogen species (RNS) which cause DNA damage and the alteration of gene expressions in both a hamster animal model and humans (Jaiswal et al, 2000;Pinlaor et al, 2003;Thanan et al, 2008;Yongvanit et al, 2012b). Regarding to the molecular mechanism underlining CCA progression, there are some studies have demonstrated aberrant expression of potential genes involving in CCA (Kunlabut et al, 2012;Namwat et al, 2012;Thongchot et al, 2014).…”

Myristoylated alanine‐rich C kinase substrate phosphorylation promotes cholangiocarcinoma cell migration and metastasis via the protein kinase C‐dependent pathway

“…(7,8) Recently, Pinlaor et al (9) suggested that oxidative and nitrosative damage to DNA in the liver of Ov-infected hamsters can play a key role in the modulation of gene expression, which enhances the effect of the DNA adduct and can drive a normal cell undergo tumor development. Additionally, Thanan et al (10) reported that the highest 8-oxodG level, which is the biomarker of DNA damage, was observed for CCA patients, and a higher level was found in the urine and leukocytes of Ov-infected patients than that in healthy patients.The gene expression profiles of Ov-associated CCA tumors, as investigated by Loilome et al(11) , indicated that myristoylated alanine-rich protein kinase C substrate (MARCKS) is significantly upregulated in tumor tissues, suggesting a role for this protein in cholangiocarcinogenesis. MARCKS is a ubiquitous heat-stable protein (12)(13)(14) that shuttles between the plasma membrane and cytoplasm in a protein kinase C (PKC) phosphorylation-dependent manner.…”

“…(7,8) Recently, Pinlaor et al (9) suggested that oxidative and nitrosative damage to DNA in the liver of Ov-infected hamsters can play a key role in the modulation of gene expression, which enhances the effect of the DNA adduct and can drive a normal cell undergo tumor development. Additionally, Thanan et al (10) reported that the highest 8-oxodG level, which is the biomarker of DNA damage, was observed for CCA patients, and a higher level was found in the urine and leukocytes of Ov-infected patients than that in healthy patients.…”