URINARY MARKERS FOR EXPOSURES TO ALKYLATING OR NITROSATING AGENTS

Investigation of urinary markers as indices of endogenous nitrosation and of gastric cancer etiology has been a major focus of our work. As part of this effort, studies have been carried out on a Colombian popu lation at high risk for gastric cancer. In this group, nitrosoproline excretion was highly correlated with nitrate excretion in the subpopul ation with advanced gastric pathology, but not in control subpopulatio ns with more normal stomachs. Neither urinary 7-methylguanine nor 3-me thyladenine was strongly related to gastric pathology or to urinary ni trate or nitrosoproline levels. More recently, as evidence has accumul ated concerning the importance of nitric oxide as a cellular messenger , we have begun research toward developing markers for the presence of nitric oxide and for endogenous nitrosation via this compound. Nitric oxide is formed from arginine by activated endothelial cells as a mes senger for vasodilation. We have shown that prolonged exercise leads t o increased urinary nitrate and that when N-15-arginine is ingested by humans, N-15-nitrate levels increase in 24-hr urine collections. Nitr osohydroxyethylglycine and 3-nitrotyrosine were evaluated as indices f or the formation of N-nitrosomorpholine and for the nitration of prote in, respectively, under experimental conditions (e.g., immunostimulati on) expected to enhance nitric oxide formation. Nitrotyrosine has not proved useful as a biomarker for nitration/nitrosation reactions in im munostimulated rats. Immunostimulation of rats following administratio n of morpholine led to increases in urinary nitrate and nitrosohydroxy ethylglycine. This procedure, however, would not be appropriate for hu mans due to the toxicity of morpholine and the carcinogenicity of N-ni trosomorpholine.