Formation of N-Nitrosamines and N-Nitramines by the Reaction of Secondary Amines with Peroxynitrite and Other Reactive Nitrogen Species:  Comparison with Nitrotyrosine Formation

Abstract

Reactive nitrogen species, including nitrogen oxides (N(2)O(3) and N(2)O(4)), peroxynitrite (ONOO(-)), and nitryl chloride (NO(2)Cl), have been implicated as causes of inflammation and cancer. We studied reactions of secondary amines with peroxynitrite and found that both N-nitrosamines and N-nitramines were formed. Morpholine was more easily nitrosated by peroxynitrite at alkaline pH than at neutral pH, whereas its nitration by peroxynitrite was optimal at pH 8.5. The yield of nitrosomorpholine in this reaction was 3 times higher than that of nitromorpholine at alkaline pH, whereas 2 times more nitromorpholine than nitrosomorpholine was formed at pH <7.5. For the morpholine-peroxynitrite reaction, nitration was enhanced by low concentrations of bicarbonate, but was inhibited by excess bicarbonate. Nitrosation was inhibited by excess bicarbonate. On this basis, we propose a free radical mechanism, involving one-electron oxidation by peroxynitrite of secondary amines to form amino radicals (R(2)N(*)), which react with nitric oxide ((*)NO) or nitrogen dioxide ((*)NO(2)) to yield nitroso and nitro secondary amines, respectively. Reaction of morpholine with NO(*) and superoxide anion (O(2)(*)(-)), which were concomitantly produced from spermine NONOate and by the xanthine oxidase systems, respectively, also yielded nitromorpholine, but its yield was <1% of that of nitrosomorpholine. NO(*) alone increased the extent of nitrosomorpholine formation in a dose-dependent manner, and concomitant production of O(2)(*)(-) inhibited its formation. Reactions of morpholine with nitrite plus HOCl or nitrite plus H(2)O(2), with or without addition of myeloperoxidase or horseradish peroxidase, also yielded nitration and nitrosation products, in yields that depended on the reactants. Tyrosine was nitrated easily by synthetic peroxynitrite, by NaNO(2) plus H(2)O(2) with myeloperoxidase, and by NaNO(2) plus H(2)O(2) under acidic conditions. Nitrated secondary amines, e.g., N-nitroproline, could be identified as specific markers for endogenous nitration mediated by reactive nitrogen species.

2′-Hydroxylation of nicotine by cytochrome P450 2A6 and human liver microsomes: Formation of a lung carcinogen precursor

“…Iminium ions such as 3, which is in equilibrium with 7, are nitrosated at neutral pH (30). Nitric oxide and peroxynitrite react with secondary amines-via N 2 O 3 , N 2 O 4 and other intermediates-to produce nitrosamines at neutral pH (31)(32)(33). Nitric oxide and peroxynitrite are formed endogenously under conditions of chronic inflammation or infection, leading to endogenous nitrosamine formation (33)(34)(35)(36), and substantial amounts of nitrogen oxides are present in cigarette smoke, resulting in endogenous nitrosamine formation in smokers (29,34,35,37).…”

Flow-injection chemiluminescent determination of nitrite in water based on the formation of peroxynitrite from the reaction of nitrite and hydrogen peroxide

“…Therefore, no CL phenomenon was observed in alkaline or neutral solution. Four different acids HCl, H 2 SO 4 , H 3 PO 4 and HNO 3 were compared. The effects of their concentrations on the CL intensity were shown in Fig.…”

“…Peroxynitrous acid is easily to be decomposed into NO 3 − and H + , it is often quenched into peroxynitrite with alkaline solution [24,25]. In the absence of NaOH, no CL signal was obtained with our CL apparatus.…”

“…When nitrite is present in water, it can react with secondary amines to form carcinogenic N-nitrosamines which are harmful to human health [3]. Furthermore, nitrite interferes with oxygen transport in the blood stream because it can convert oxyhemoglobin into metahemoglobin.…”

Emissions to the Atmosphere from Amine-Based Post Combustion CO2Capture Plant – Regulatory Aspects

“…Nitrosamines and nitramines were reported as possible degradation products resulting from the interaction between organic amines and nitrosating agents such as nitrate and nitrite (Masuda et al, 2000;Azzi, 2009, 2010; Brakstad et al, 2010; Pedersen et al, 2010).…”