Evaluation of the nitrosamine hypothesis of gastric carcinogenesis in precancerous conditions.

Abstract

SUMMARY A 24 hour gastric aspiration study was carried out on nine Polya gastrectomy, eight pernicious anaemia, and nine matched control subjects. Intragastric pH, bacteria, nitrite, and Nnitroso compounds were assessed half hourly whilst ambulant and hourly when in bed. Both total and nitrate reducing bacterial counts were positively related to pH (x2=279-3; p<0.001), as was nitrite concentration (F=19.1; p<00001). By contrast, total (F=40.6; p<00001) and stable (F=257.4; p<0.0001) N-nitroso compound concentrations were negatively related to pH. Clear differences in these gastric juice factors were not apparent between matched control and either pernicious anaemia, or Polya gastrectomy because the Polya gastrectomy and matched control groups were heterogeneous for gastric acidity. Thus, although eight of eight pernicious anaemia subjects were hypoacidic (defined as intragastric pH >4 for >50% of both daytime and night time periods), only five of nine Polya gastrectomy and two of nine matched control subjects were hypoacidic. When subjects were rearranged into hypoacidic (n=15) and acidic (n=11) groups, bacterial counts (p<0.01) and nitrite concentrations (p<0.01) were higher, whereas Nnitroso compounds tended to be lower (NS) in the hypoacidic group. These data suggest that, although hypoacidity predisposes to bacterial overgrowth and nitrite generation, it does not enhance nitrosation. Instead, this is maximal at low pH, suggesting chemical rather than bacterial nitrosation, contrary to the nitrosamine hypothesis of gastric carcinogenesis.The incidence of hypochlorhydria has been reported to be as high as 85-90% in gastric cancer,1 2 and it has been shown that hypochlorhydria may precede gastric cancer by several years.3 The hypochlorhydric states of Polya gastrectomy (15 years after surgery) and pernicious anaemia78 are accompanied by an increased incidence of gastric cancer, and are considered to be precancerous conditions.9The nitrosamine hypothesis of gastric carcinogenesis postulates that high intragastric pH in hypochlorhydria promotes the growth of bacteria which reduce dietary nitrate to nitrite and then convert dietary amines, in the presence of this nitrite, into N-nitroso compounds.'( 11 N-nitroso compounds are proven carcinogens in all mammalian species tested, 12 and may initiate cellular mutations of increasing serverity in the human stomach eventually culminating in cancer.

N-Nitroso Compounds, Bacteria, and Carcinoembryonic Antigen in the Gastric Stump

“…Among reports on gastric juice NOC assays in patients with partial gastrectomy for peptic ulcer [3, 18, 20 -24], the data reported by Schlag et al [3] and Sturniolo et al [25] were criticized because of inadequate analytical methods [26,28]. In the controversy about NOC production in the hypochlorhydric stump, our data confirm previous observations [23,26] relating increased NOC levels with pH elevation in Billroth II patients, a correlation not observed by others [21,24,27]. Our data support the findings of Reed et al [23], as we also found significantly higher mean gastric juice NOC levels in patients with gastric resections compared with normal controls.…”

“…Our data support the findings of Reed et al [23], as we also found significantly higher mean gastric juice NOC levels in patients with gastric resections compared with normal controls. This was not observed by other authors [21,24,27] who claimed that the postulated role of NOCs in the Correa multistage hypothesis of gastric carcinogenesis required further confirmation. In our opinion, the contradictions to the reported data are due to four reasons: (a) different sampling modalities; (b) different analytical methods; (c) different time intervals between sample collection and analysis; (d) a lack of patient homogeneity.…”

“…Of the control subjects reported by Hall et al [24], 35-48% had a gastric juice pH Ͼ 4 and bacterial contamination was present in 55-85%. Keighley et al [21] and Morris et al [27] did not specify if their control subjects had normal gastric histology.…”

The Achlorhydria-Carcinoid Sequence: Role of Gastrin

“…However, the nitrosamine hypothesis is unproven, and has recently been criticized, because nitrosation is chemically rather than bacterially me diated, i.e. favoured by low rather than high pH [28,29]. This cannot be discussed further in the framework of this review.…”

Carcinogenic potential of duodenal reflux juice from patients with long-standing postgastrectomy

“…This "N-nitroso compounds" theory has provided a potential explanation for some geographic regions at a very high risk for gastric cancer [29] . But whether this theory can work as well to interpret the high incidence of gastric cancer in the postgastrectomy patients is still a matter of dispute [30][31][32][33][34] . Although we did not measure the concentrations of N-nitroso compounds directly, the initiating assay can effectively detect the mutagenicity of the whole human reflux juice that may contain various mutagenic or carcinogenic substances inclusive of the N-nitroso compounds.…”