Novel mechanism of nitrosative stress from dietary nitrate with relevance to gastro-oesophageal junction cancers

Iijima, K., Grant, J., McElroy, K., Fyfe, V., Preston, T. and McColl, K.E.L. (2003) Novel mechanism of nitrosative stress from dietary nitrate with relevance to gastro-oesophageal junction cancers. Carcinogenesis, 24(12), pp. 1951-1960. (doi:10.1093/carcin/bgg168)

Iijima, K., Grant, J., McElroy, K., Fyfe, V., Preston, T. and McColl, K.E.L. (2003) Novel mechanism of nitrosative stress from dietary nitrate with relevance to gastro-oesophageal junction cancers. Carcinogenesis, 24(12), pp. 1951-1960. (doi:10.1093/carcin/bgg168)

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Abstract

High luminal concentrations of nitric oxide are generated at the human gastro-oesophaegal junction and within Barrett's oesophagus due to the reduction of salivary nitrite to nitric oxide by acidic gastric juice. Salivary nitrite is derived from the entero-salivary recirculation of dietary nitrate. Our aim was to determine whether nitric oxide generated within the lumen will exert nitrosative stress on the adjacent epithelium. A benchtop model was constructed reproducing the nitrite chemistry occurring within the lumen of the upper gastrointestinal tract where saliva encounters acidic gastric juice. It incorporated an epithelial compartment maintained at pH 7.4 and separated from the lumen by a hydrophobic barrier with the properties of the epithelial lipid cell membrane. The secondary amine morpholine was used to measure N-nitroso compound formation in both the lumen and epithelial compartment. Adding 100 muM nitrite to the acidic (pH 1.5) luminal compartment depleted of ascorbic acid generated 6.2 +/- 2.0 muM (mean +/- SE) N-nitrosomorpholine in that compartment and 2.2 +/- 0.1 muM nitrosomorpholine in the epithelial compartment at 30 min. When 100 muM nitrite was added to the acidic luminal compartment containing physiological concentrations of ascorbic acid, all the nitrite was immediately converted to nitric oxide and no N-nitrosomorpholine was formed within that compartment. However, the nitric oxide rapidly diffused from the luminal compartment into the epithelial compartment and there generated very high concentrations of N-nitrosomorpholine (137 +/- 5.6 muM at 30 min). The addition of ascorbic acid or glutathione to the epithelial compartment could only reduce nitric oxide-induced nitrosation within that compartment by 40%. The nitrate-derived nitric oxide generated within the lumen where saliva encounters gastric acid is likely to exert substantial nitrosative stress on the adjacent epithelium. This may contribute to the high prevalence of mutagenesis at this anatomical site.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Preston, Professor Thomas and McColl, Professor Kenneth
Authors: Iijima, K., Grant, J., McElroy, K., Fyfe, V., Preston, T., and McColl, K.E.L.
Subjects:R Medicine > R Medicine (General)
R Medicine > RC Internal medicine
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Science and Engineering > Scottish Universities Environmental Research Centre
Journal Name:Carcinogenesis
ISSN:0143-3334
Published Online:11 September 2003

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