Neutrophil-mediated formation of carcinogenic N-nitroso compounds in an in vitro model for intestinal inflammation.
In order to study neutrophil-mediated formation of carcinogenic N-nitroso compounds as a mechanism of inflammation-related colon carcinogenesis, we designed an in vitro model for intestinal inflammation, consisting of a coincubation system with human colon cells (Caco-2 cells) and activated human neutrophils (PMN), as important immunoreactive cells. We investigated whether nitrosamines and nitrosamides could be formed upon addition of dimethylamine, morpholine and methylurea to the coincubations as nitrosatable precursors, which are known to produce carcinogenic N-nitroso compounds. Incubations of pure nitric oxide with dimethylamine and morpholine showed that NO-mediated formation of nitrosodimethylamine and nitrosomorpholine is possible under the incubation conditions. During the coincubations of activated PMN and Caco-2 cells, 0.34 nmol nitrite/10(6) PMN was produced. Dose-dependent formation of NMOR was observed in this PMN/Caco-2 system; addition of 5mM morpholine resulted in a significantly increased NMOR formation of 4.2 nM. However, no detectable NDMA and methylnitrosourea were formed in this coincubation system. These results suggest that activated human neutrophils are able to synthesize carcinogenic N-nitrosamines, e.g. NMOR, which implies a risk of colon carcinogenesis during chronic inflammation. However, the observed relatively low level of nitrosation suggests that also other risk factors are contributing to the association between chronic inflammation and colon cancer risk.
Vermeer
Ingrid T M
IT
Department of Health Risk Analysis and Toxicology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
Henderson
Laila Y
LY
Moonen
Edwin J C
EJ
Engels
Leopold G J B
LG
Dallinga
Jan W
JW
van Maanen
Jan M S
JM
Kleinjans
Jos C S
JC
D018938:Caco-2 Cells; D002273:Carcinogens / Q000378:metabolism*; D003092:Colitis / Q000150:complications*; D003110:Colonic Neoplasms / Q000209:etiology*; D018736:DNA Adducts / Q000378:metabolism; D006801:Humans; D018375:Neutrophil Activation; D009504:Neutrophils / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis; D009573:Nitrites / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism; D009603:Nitroso Compounds / Q000378:metabolism*
D002273:Carcinogens; D018736:DNA Adducts; D009573:Nitrites; D009602:Nitrosamines; D009603:Nitroso Compounds; D009569:Nitric Oxide