Vitamin C as a nitrosation inhibitor: A modelling study across dietary patterns and water quality.

Rising dietary and drinking-water intake of nitrate (NO3-) and nitrite (NO2-) presents a significant public health concern. After ingestion, a portion of NO3- enters the enterosalivary circulation, where oral bacteria reduce it to NO2-. When swallowed, NO2- enters the acidic gastric environment, where it can react to form N-nitroso compounds (NOCs), many of which are suspected carcinogens. However, epidemiological evidence for this link remains mixed, likely due to the protective effects of antioxidants such as vitamin C, which is present in many high-NO3- foods (e.g. leafy vegetables). To better understand and quantify these complex interactions, we develop a dynamic, compartmental quantitative systems pharmacology (QSP) model of human NO3- and NO2- metabolism and gastric chemistry. The framework tracks NO3- and NO2- fluxes across the stomach, intestine, plasma, and saliva, incorporates postprandial changes in gastric volume and pH, and includes mechanistic nitrosation pathways with vitamin C inhibition. Using this model, we evaluate NOC formation under different dietary and water-quality contexts, demonstrating the protective effect of dietary vitamin C and investigating the role of vitamin C supplementation in suppressing NOC formation. Our simulations suggest, across all dietary contexts, supplementation is most effective when administered shortly after each meal. These findings provide a mechanistic basis for understanding how diet, drinking-water NO3- and NO2-, and vitamin C supplementation interact to shape endogenous NOC formation, with potential implications for nutritional guidelines and risk mitigation in vulnerable populations.