Increased nitrosamine and nitrate biosynthesis mediated by nitric oxide synthase induced in hamsters infected with liver fluke (Opisthorchis viverrini).
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.
Ohshima
H
H
Unit of Environmental Carcinogens and Host Factors, International Agency for Research on Cancer, Lyon, France.
Bandaletova
T Y
TY
Brouet
I
I
Bartsch
H
H
Kirby
G
G
Ogunbiyi
F
F
Vatanasapt
V
V
Pipitgool
V
V
D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D000818:Animals; D002347:Carps; D006224:Cricetinae; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology; D008297:Male; D008647:Mesocricetus; D009566:Nitrates / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D009602:Nitrosamines / Q000378:metabolism*; D009603:Nitroso Compounds / Q000652:urine; D009889:Opisthorchiasis / Q000378:metabolism*; D009891:Opisthorchis; D013844:Thiazoles / Q000652:urine; D053778:Thiazolidines
D009566:Nitrates; D009602:Nitrosamines; D009603:Nitroso Compounds; D013844:Thiazoles; D053778:Thiazolidines; C040387:N-nitrosothiazolidine-4-carboxylic acid; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases