Inhibition of bacterially mediated N-nitrosation by ascorbate: therapeutic and mechanistic considerations

Abstract

Ascorbate is known to inhibit the acid-catalysed N-nitrosation reactions of nitrite in the normally acid stomach, suggesting a useful therapeutic application of this compound to reduce exposure to the carcinogenic products of such reactions. However, in the achlorhydric stomach, which is particularly predisposed to cancer, increased exposure to endogenous N-nitroso compounds may result from bacterially catalysed reactions. The mechanism of these bacterially mediated reactions is only just beginning to be understood, and, indeed, more than one such mechanism may exist. Despite its usual lack of reactivity towards nitrite at neutral pH, ascorbate proved to be a potent inhibitor of the bacterially mediated (Pseudomonas aeruginosa) nitrosation of morpholine, competing with morpholine for the nitrosating agent elaborated by the bacteria from nitrite (the kinetics of the inhibition were classically competitive). This and other data, particularly with regard to the dependence of the bacterially mediated reaction on amine pKa, are discussed in relation to the potential mechanisms of these bacterially mediated reactions.