Increased nitrosamine and nitrate biosynthesis mediated by nitric oxide synthase induced in hamsters infected with liver fluke (Opisthorchis viverrini)

Abstract

We previously reported that increased endogenous nitrosation in human subjects infected with the liver fluke Opisthorchis viverrini in north-east Thailand could be a risk factor for the development of cholangiocarcinoma. In the present study we examined our hypothesis that this increased endogenous nitrosation is mediated by nitric oxide (NO) synthase induced by O. viverrini infestation. Syrian golden hamsters experimentally infected with O. viverrini liver fluke excreted in the urine significantly greater amounts of nitrate, a stable oxidization product of NO, than untreated hamsters (3.64 +/- 0.86 versus 2.64 +/- 0.60 mumol/hamster/day, P < 0.001). When the rapidly nitrosatable thiazolidine 4-carboxylic acid was administered orally, the infected hamsters also excreted significantly elevated levels of N-nitrosothiazolidine 4-carboxylic acid than untreated hamsters (4.27 +/- 2.20 versus 2.33 +/- 1.13 nmol/hamster/day, P < 0.01), indicating that endogenous nitrosation is elevated in the animals with liver fluke. NO synthase activity measured in liver cytosol was about twice as high in the infected hamsters as in untreated animals. The enzyme, whose biochemical characteristics were similar to that induced in activated murine macrophages, was immunohistochemically localized in the cytoplasm of macrophages and eosinophils in the inflammation zone surrounding the parasite-containing bile ducts. These results support our hypothesis that, in fluke-infected subjects, NO synthase induction leads to excess production of NO and the observed elevated endogenous nitrosation. Since high concentrations of NO exert cytotoxic and mutagenic effects per se, excess NO produced in chronically infected/inflamed tissues may also play a role in initiation and subsequent modulation stages of cholangiocarcinoma development.

Chronic Hepatitis, Hepatic Dysplasia, Fibrosis, and Biliary Hyperplasia in Hamsters Naturally Infected with a Novel Helicobacter Classified in the H. bilis Cluster

“…The findings of that epidemiologic study are supported by the observation that patients infected with liver flukes have increased urinary secretion of nitrate and N-nitrosoproline, and the authors argued that the combination of fluke infection plus nitrosamine exposure increased the risk of development of cholangiocarcinoma in the Thai population (43,44). These data are also consistent with the observation that hamsters infected with O. viverrini had increased levels of nitrosamine and nitrate biosynthesis mediated by nitric oxide synthase (32). Repeated infection with O. viverrini also induced inflammation-associated DNA damage in the bile ducts of hamsters via inducible nitric oxide synthase (24,34).…”

Chronic bacterial and parasitic infections and cancer: a review

“…Accordingly, this hyperplastic epithelium might be vulnerable to various exogenous and endogenous carcinogens [127,128]. Moreover, activation of drug metabolizing enzymes (such as p-450) as well as increased nitric oxide production can result in DNA damage [129,130] and cytotoxicity [112,128,131], respectively.…”

Characterisation of S‐nitrosohaemoglobin by mass spectrometry

“…In addition, NO produced in infected and inflamed tissue could contribute to the process of carcinogenesis [4,5]. Although NO has been known since the late 1970s to be among the ligands that activate soluble guarníate cyclase and cause vascular smooth muscle relaxation, it has not been appreciated until more recently that NO is also an endogenous vasorelaxant.…”