Oxidative and nitrative DNA damage: Key events in opisthorchiasis-induced carcinogenesis

Chronic inflammation induced by liver fluke (Opisthorchis viverrini) infection is the major risk factor for cholangiocarcinoma (CCA) in Northeastern Thailand. Increased levels of proinflammatory cytokines and nuclear factor kappa B that control cyclooxygenase-2 and inducible nitric oxide activities, disturb the homeostasis of oxidants/anti-oxidants and DNA repair enzymes, all of which appear to be involved in O. viverrini-associated inflammatory processes and CCA. Consequently oxidative and nitrative stress-related cellular damage occurs due to the over production of reactive oxygen and nitrogen species in inflamed target cells. This is supported by the detection of high levels of oxidized DNA and DNA bases modified by lipid peroxidation products in both animal and human tissues affected by O. viverrini-infection. Treatment of opisthorchiasis patients with praziquantel, an anti- trematode drug was shown to reduce inflammation-mediated tissue damage and carcinogenesis. The principal mechanisms that govern the effects of inflammation and immunity in liver fluke-associated cholangiocarcinogenesis are reviewed. The validity of inflammation-related biomolecules and DNA damage products to serve as predictive biomarkers for disease risk evaluation and intervention is discussed.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideResearch highlights► Chronic inflammation induced by liver fluke infection is the major risk factor for cholangiocarcinoma. ► Persistent oxidative/nitrative stress disturbs homeostasis of adaptive response systems. ► Overproduction of reactive oxygen and nitrogen species leads to genotoxic DNA damage. ► Mechanisms that link O. viverrini infection to the onset of tumorigenesis are reviewed. ► Predictive biomarkers for disease risk evaluation and intervention are discussed.