Carcinogenesis Advance Access published online on September 11, 2003
Carcinogenesis, doi:10.1093/carcin/bgg168
© 2003 by Oxford University Press
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CARCINOGENESIS
1 Department of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
* Corresponding author. E-mail: K.E.L.McColl{at}clinmed.gla.ac.uk.
Received 3 June 2003
; revised 25 August 2003
; accepted 27 August 2003
High luminal concentrations of nitric oxide are generated at the human gastroesophaegal (GE) junction and within Barrett's esophagus 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. AIMS To determine whether nitric oxide generated within the lumen will exert nitrosative stress on the adjacent epithelium. METHODS A benchtop model was constructed reproducing the nitrite chemistry occurring within the lumen of the upper GI tract where saliva encounters acidic gastric juice. It incorporated an epithelial compartment maintained at pH7.4 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. RESULTS Adding 100µM nitrite to the acidic (pH1.5) luminal compartment depleted of ascorbic acid generated 6.2±2.0µM (mean±SE) N-nitrosomorphine in that compartment and 2.2±0.1µM nitrosomorpholine in the epithelial compartment at 30 min. When 100µM 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±5.6µM 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%. CONCLUSION 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.
N-nitroso compounds, cancer, Barrett's, nitric oxide, nitrite, nitrate, diet, gastro-oesophageal junction
Novel mechanism of nitrosative stress from dietary nitrate with relevance to gastroesophageal junction cancers
2 Section of Medicine, Western Infirmary, 44 Church Street, Glasgow, G11 6NT, Scotland, UK
3 Scottish Universities Environmental Research Centre, East Kilbride, Glasgow, G75 0QF, Scotland, UK
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