THIOCYANATE-INDEPENDENT NITROSATION IN HUMANS WITH CARCINOGENIC PARASITE INFECTION

I nfection with the liver fluke, Opisthorchis viverrini, is a causativ e agent of cholangiocarcinoma. One possible contributing factor in thi s carcinogenesis is the chronic, local generation of nitric oxide by i nflammatory cells expressing inducible nitric oxide synthase and the p roduction of N-nitroso compounds via the reaction between amines and n itrosating agents derived from nitric oxide, Our previous studies prov ided evidence that nitric oxide synthesis is elevated during human Liv er fluke infection, Here we present data on the same sample of men whi ch definitively demonstrates increased nitrosation of proline and thio proline (thiazolidine-4-carboxylic acid) among infected men compared t o uninfected control subjects on a low nitrate diet, This difference w as specifically abolished by co-administration of ascorbic acid with p roline and by elimination of parasites by praziquantel treatment, Mult ivariate statistical models demonstrate the importance of salivary thi ocyanate levels to variation in the nitrosation of proline among uninf ected individuals, but not among those with current fluke infection, T his suggests that considerable generation of nitrosating agents (N2O3/ N2O3) in infected people may be occurring via oxidation of arginine by nitric oxide synthase in inflamed tissue which is thiocyanate insensi tive, Analyses revealed positive associations between N-nitrosoproline excretion and nitrate/nitrite levels in urine, plasma and saliva and with usual alcohol intake; with variation in these trends between grou ps, In conclusion, we have confirmed the relationship between O.viverr ini infection and enhanced endogenous nitrosation, showing evidence of its extragastric site, New information is also provided on the determ inants of N-nitrosamino acid excretion in men on a controlled low nitr ate diet without smoking, conditions which reduce exogenous sources of nitrosating agents.