Endogenous incorporation of nitric oxide from L-arginine into N-nitrosomorpholine stimulated by Escherichia coli lipopolysaccharide in the rat

Abstract

The endogenous formation of nitrate in the rat, mouse and human occurs through cellular processes involving the oxidation of the guanido group of arginine. These processes proceed from arginine to nitric oxide with subsequent conversion to electrophilic nitrosating agents capable of forming carcinogenic nitrosamines. We have now demonstrated that endogenous nitrosamine formation can occur via cells stimulated in vivo by bacterial lipopolysaccharide (LPS). The nitrosation of morpholine given to rats by i.p. injection yields N-nitrosomorpholine (NMOR) which is subsequently oxidized in the liver. A major metabolite of NMOR, N-nitroso-(2-hydroxyethyl)glycine, was previously shown by other investigators to be excreted into urine. Treatment of rats with LPS, arginine and morpholine creates a large increase in NMOR urinary metabolites over a 24-h period. This process is not influenced by simultaneous dosage with large amounts of NaNO3. Therefore the endogenous LPS-induced formation of NMOR proceeds directly from nitric oxide prior to incorporation into the nitrate body pool. The proportion of endogenously synthesized nitric oxide incorporated into NMOR is approximately 3 x 10(-6).