The influence of dietary nitrate and acid suppression on the intragastric environment and the risk of carcinogenesis

Mowat, Craig (2000) The influence of dietary nitrate and acid suppression on the intragastric environment and the risk of carcinogenesis. MD thesis, University of Glasgow.

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Abstract

In 1975, Correa's original hypothesis for gastric carcinogenesis proposed that atrophic gastritis leads to achlorhydria and secondary colonisation of the stomach with nitrosating bacteria. These organisms reduce dietary nitrate to nitrite, then catalyse the synthesis of potentially carcinogenic N-nitroso compounds (NOC) from nitrite and secondary amines present in gastric juice. Since then, significant advances have been made in our understanding of gastric physiology which are also relevant to our understanding of gastric carcinogenesis. Helicobacter pylori (H. pylori) infection is now a recognised risk factor for gastric carcinogenesis. If it produces a pangastritis, there is an associated degree of gland-loss (atrophy) of the acid-secreting body of the stomach. Atrophic gastritis is a precursor of the development of gastric cancer. H. pylori infection also lowers levels of vitamin C, which is secreted into and concentrated within gastric juice. The synthesis of NOC is inhibited by vitamin C. Advances in the treatment of acid-related disorders have resulted in the prescription of increasingly potent inhibitors of acid secretion. The proton pump inhibitors (PPI's) render H. pylori infected subjects achlorhydric from one dose to the next. They also promote the development of a pangastritis. Whether these effects are harmful in the long term remains hotly debated. Two recent reports suggest that long term PPI therapy does lead to development of moderate-severe atrophy of the gastric body in ~18% of H. pylori infected subjects, compared to 0 - 2% of no-infected subjects, thereby placing these patients at risk of gastric cancer. There are great concerns that the falling incidence of gastric cancer in the developed world may be reversed by widespread prescription of these agents. How PPI's produce gastric atrophy in H. pylori infected patients remains to be elucidated. This thesis postulates that, in the presence of co-existing H. pylori infection, drug-induced achlorhydria alters the intragastric environment in a way that will facilitate bacterial synthesis of carcinogenic NOC which in turn may damage gastric epithelial stem cell DNA. The thesis begins by re-examining the roles of nitrate, nitrite and vitamin C in man. The enterosalivary recirculation of ingested nitrate is described, whereby dietary nitrate is reduced to nitrite in saliva to provide the main source of nitrite to the upper GI tract. The important chemical interactions between nitrite and ascorbic acid in vitro are described with reference to NOC synthesis. NOC synthesis is promoted by a high nitrite : ascorbic acid ratio. The in vivo interactions between saliva nitrite and gastric ascorbic acid are speculated upon and the potential effects of PPI-induced achlorhydria and H. pylori infection on these interactions are considered. To begin, novel studies infused nitrite into the acid stomach to mimic salivary nitrite influx following a nitrate meal. These studies demonstrate for the first time in vivo the interaction between nitrite and vitamin C in the gastric lumen. Gastric juice ascorbic acid is depleted and in the process is converted to dehydroascorbic acid. Nitrite is lost from solution - presumably as nitric oxide. These novel studies were repeated, replacing the nitrite infusion with a solution of nitrate to mimic the effects of ingesting a portion of lettuce. These studies confirm that ingestion of nitrate leads to elevation of saliva nitrite levels via the process of enterosalivary recirculation. (Abstract shortened by ProQuest.).

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: Kenneth McColl
Keywords: Nutrition, Oncology
Date of Award: 2000
Depositing User: Enlighten Team
Unique ID: glathesis:2000-72773
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 11 Jun 2019 11:06
Last Modified: 11 Jun 2019 11:06
URI: http://theses.gla.ac.uk/id/eprint/72773

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