Goldman et al.[75] showed NO mediated inhibition of the activity of the sodium/hydrogen exchanger that can pump protons out of cells to maintain intracellular pH. Subsequently, intracellular acidification induced NO exposure that led to DNA damage,

toxicity, and neoplastic development. In addition, Proteases inhibitor there have been several animal model studies that investigated the involvement of NO in the pathogenesis of esophageal carcinogenesis. Accumulating previous animal model studies demonstrated that administering nitrite with ascorbic acid or other anti-oxidants to rats induced tumors in their forestomach, which is contiguous with the esophagus and lined by squamous epithelium.[76-78] The tumors did not occur if only nitrite was administered. Hence, the combination of nitrite and anti-oxidants generated a high concentration of NO, which had a mutagenic effect on the epithelium.[79] Kuroiwa et al.[80] extended these studies by showing that administration of exogenous NO (sodium nitrite plus ascorbic acid) to an acid-type reflux model of rat induced esophageal squamous cell carcinoma, although the treatment failed to induce the development of Barrett’s esophagus or esophageal adenocarcinoma. This study may indicate that NO alone in the absence of refluxed duodenal

contents is incapable of causing columnar transformation of the esophagus, although buy Venetoclax the treatment might elicit squamous carcinogenesis. In another study, Kumagai et al.[81] demonstrated that thioproline (a nitrite scavenger)

inhibited the development of esophageal adenocarcinoma by gastroduodenal reflux in rats, suggesting the involvement of reactive nitrogen species such as NO, peroxynitrite, and nitroso compounds in the pathogenesis of esophageal adenocarcinoma. Since the 1980s, MCE numerous studies have shown that the incidence of esophageal adenocarcinoma has been increasing rapidly in many western countries; however, the precise cause for the cancer endemic remains unclear.[82] In terms of a mass survey, a 20-fold increase in use of chemical nitrogenous fertilizers and associated increased dietary nitrate exposure post-war may be potentially responsible for the marked increase in the incidence of the esophageal adenocarcinoma.[10, 11, 20] Thus far, epidemiological studies have not shown an association of nitrate intake with esophageal adenocarcinoma.[83, 84] Additionally, a recent epidemiological study has demonstrated a paradoxical association between nitrate intake and Barrett’s esophagus depending on gender, that is, total nitrate intake was inversely associated with Barrett’s esophagus in men, while it was positively associated with the pre-malignant condition in women.[85] These studies may suggest that individual susceptibility to esophageal adenocarcinoma does not depend on nitrate intake. However, other co-factors are also closely involved in the chemical reaction of luminal NO generation in the lower esophagus.