GASTRIC FORMATION OF N-NITROSO COMPOUNDS

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Long-term Objective: Elucidation of dietary and physiological variables in endogenous N-nitroso compound formation so that the in vivo formation of these carcinogens can be reduced or eliminated through dietary modification. The result will be a diminished human cancer risk. Specific Aims: 1) To quantify endogenous formation of mutagens and carcinogenic N-nitroso compounds during gastric digestion and to relate these rates to the formation of noncarcinogenic markers of in vivo nitrosation (nitrosoproline). 2) To determine if the stomach is the sole site of endogenous nitrosation and the importance of endogenous precursors (nitrate and amines) compared to dietary precursors. 3) To quantify the inhibitory effects of ascorbic acid and to determine the effect of the time of administration of precursors and inhibitor. 4) To determine if transnitrosation contributes to in vivo N-nitroso compound formation. 5) To determine the effects of stomach pH and bacterial colonization on in vivo N-nitrosation. 6) To compare "high" and "low" gastric cancer risk foods for mutagen and N-nitroso compound formation during digestion. Methodology: Four 20 to 70 kg pigs with surgically implanted stomach fistula will be treated with known amine or amide precursors of endogenous N-nitroso compounds and known or suspected nitrosating agents. Stable isotopes of precursors will be utilized. A nonabsorbable marker will be added to the gastric contents at a known concentration so that the volume of gastric contents lost to the lower tract can be determined. Gastric fluid samples will be withdrawn by catheter at 30 min intervals for 4 hours after test administration and in most experiments quantitatively analyzed for the marker, mutagenic activity (bacterial), volatile N-nitroso compounds, N-nitrosoamino acids, NO3-, NO2-, N-nitrosomethylurea, ascorbate, and isotopic ratios. In some experiments, animals will be treated with ascorbic acid at various relative times and with different amounts prior to administration of N-nitroso precursors. Physiological variables will be tested by altering the stomach pH and by establishing gastric bacterial colonies. "Meals" high in salted dried fish, cured pork, complex starches from wheat and absent in leafy vegetables, fruits and vitamin C will be compared to meals containing fresh fruits and vegetables. Gastric contents from each food type will be assayed.