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- N-nitroso compounds
- inflammatory bowel disease
- N -nitrosodimethylamine
- inducible nitric oxide synthase
- colon cancer
In patients with inflammatory bowel disease (IBD), an increased incidence of colorectal cancer is observed.1 Although severe inflammatory conditions per se represent a risk factor for neoplasia, we would like to draw attention to the possible role of increased activity of inducible nitric oxide synthase (iNOS), as found in IBD patients,2 in the endogenous formation of carcinogenic N-nitroso compounds (NOC). In healthy individuals, relatively small amounts of NOC are formed by the interaction between NOC precursors (NOCP), present in dietary items such as meat and fish, and nitrosating agents derived from dietary nitrate. It has been proposed that endogenous formation of NOC may explain the link between meat consumption and colon cancer risk found in epidemiological studies.3 We hypothesised that as a result of chronic inflammatory conditions in the large intestine, increased colonic iNOS activity may produce an excess of NO, nitrogen oxides, and nitrite, which in turn react with NOCP present in the colon to produce relatively high levels of NOC. Increased formation of NOC in IBD patients may thus contribute to the relatively high incidence of colorectal cancer associated with this disease.
A recent population based case control study showed that in cases with a history of IBD, increased exposure to drinking water nitrate was associated with an increased risk of colon cancer whereas no such association was found in the overall population.4 This clearly indicates that the risk of colon cancer in IBD patients is not only determined by the disease itself but dietary factors known to influence the endogenous formation of NOC are also associated with an increased risk in these patients. Although both the increased formation of NOC found in mice with chemically induced colitis5 and increased levels of NO and nitrite found in the colonic lumen of patients with ulcerative colitis6 support this hypothesis, faecal NOC levels have never been investigated in IBD patients.
Therefore, we collected faecal samples from 17 patients diagnosed with ulcerative colitis and 17 healthy controls, and determined levels of N-nitrosodimethylamine (NDMA), a predominant carcinogenic NOC, using gas chromatography-mass spectrometry, as previously described.7 The study was approved by the medical ethics committee of the Maasland Hospital, Sittard, the Netherlands, and all patients gave their consent. In 41% of patients, we found levels of NDMA above the detection limit of 1 ng/g faeces, compared with 35% of controls. Comparison of concentrations in NDMA positive samples showed that the average concentration in patients was significantly higher than that in the control group (table 1). When IBD patients were subdivided into hospitalised and non-hospitalised cases, the difference between the non-hospitalised group and controls was even more pronounced, whereas NDMA concentrations in hospitalised patients and controls were comparable. As all hospitalised patients received only liquid nutrition (Nutrison; Nutricia, UK) without additional intake of NOCP rich dietary foods, these results confirm that the combination of high dietary NOCP intake and inflammation may present a risk factor.
Most research on endogenous NOC exposure has focused predominantly on the intragastric formation of these compounds in relation to the gastric cancer risk. However, we now report that faecal NDMA levels in IBD patients are considerably higher than those we reported previously in gastric juice (0.25 (0.3) ng/g),7 which indicates that NOC exposure may be even more relevant in colon carcinogenesis.
Based on these results, we conclude that the colon of IBD patients is exposed to relatively high concentrations of this carcinogenic compound, probably as a direct consequence of continuous NO production by the inflammatory process. As this exposure may strongly contribute to the increased colon cancer risk associated with IBD, dietary recommendations for IBD patients, avoiding high NOCP intake, seem warranted.
Conflict of interest: None declared.