TY  - JOUR
A1  - Shephard, S. E.
A1  - Lutz, Werner K.
T1  - Nitrosation of dietary precursors
N2  - The diet contains a large number of constituents which can be nitrosated in the gastrointestinal tract (especially in the stomach) to potentially carcinogenic nitroso compounds (NOC). The nitrosation of food mixtures has been investigated with a number of assays, such as chemical analysis or detection of alkylating potential, mutagenicity and carcinogenicity. Relatively good information is available on the formation of stable nitrosamines using high nitrite concentrations. Little is known, however, about the formation of chemically unstable NOC at low nitrite concentration and their genotoxicity in target cells. A comparison of the precursor classes, alkylamines, aromatic amines, amino acids, amides and peptides, ureas and guanidines, reveals a vast range, both with respect to daily intake (105-fold) and nitrosation rate (104-fold both for 1st and 2nd order nitrite dependence). A total span of 108 results for the relative yield of NOC in the stomach. The endogenous NOC burden from dietary ureas and aromatic amines may represent as large a hazard as the intake of preformed NOC. Recent evidence also indicates that heterocyclic amines and phenols must be considered and that the half-life of nitrosated a-amino acids can be much longer than that of nitrosated primary alkylamines. In these classes, more information should be collected on dietary concentrations, on the nitrosation under realistic conditions and on the genotoxicity in stomach lining cells. Within a chemical precursor class, a wide range is seen with respect to alkylating potency. It cannot, therefore, be excluded that individual precursors within the top ranking classes might become more important than single preformed NOC. Not considered in the above analysis but probably just as important for a risk evaluation in a population is the knowledge of the nitrosation conditions and target cell susceptibility in individuals.
KW  - Ernährung
KW  - diet
KW  - amine
KW  - amino acid
KW  - urea
KW  - nitrosation
KW  - nitroso compound
KW  - endogenous
KW  - stomach
KW  - alkylation
KW  - 4-(p-nitrobenzyl)pyridine
KW  - DNA binding
KW  - genotoxic
KW  - mutagen
KW  - carcinogen
KW  - Nitrosierung
Y1  - 1989
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-70311
ER  - 
TY  - JOUR
A1  - Meier, I.
A1  - Shephard, S. E.
A1  - Lutz, Werner K.
T1  - Nitrosation of aspartic acid, aspartame, and glycine ethylester. Alkylation of 4-(p-nitrobenzyl)pyridine (NBP) in vitro and binding to DNA in the rat
N2  - In a colorimetric assay using 4-( p-nitrobenzyl)pyridine (NBP) as a nucleophilic scavenger of alkylating agents, the nitrosation and alkylation reactions were investigated for a number of amino acids and derivatives. The alkylating activity increased with the square of the nitrite concentration. The nitrosation rate constants for aspartic acid, aspartame, and glycine ethylester ( = precursors C) were 0.08, 1.4 and ~ 0.2, respectively, expressed in terms of the pH-dependent \(k_2\) rate constant of the equation dNOCjdt = \(k_2\) • (C]· [nitrite]\(^2\) • The rates correlated inversely with the basicity of the amino group. The stability of the alkylating activity was astonishingly high, both in acid and at neutral pH. Half-lives of 500, 200, and 30 min were determined for aspartic acid (pH 3.5), aspartame (pH 2.5), and glycine ethylester (pH 2.5). Values of 60, 15, and 2 min; respectively, were found at pH 7. It is concluded that rearrangement of the primary N-nitroso product to the ultimate alkylating agent could be rate-limiting. The potential of nitrosated a-amino acids to bind to DN A in vivo was investigated by oral gavage of radiolabelled glycine ethylester to rats, followed irnmediately by sodium nitrite. DNA was isolated from stomach and liver and analysed for radioactivity and modified nucleotides. No indication of DNA adduct formation was obtained. Based on an estimation of the dose fraction converted from glycine ethylester to the nitroso product under the given experimental conditions, the maximum possible DNA-binding potency of nitroso glycine ethylester is about one order of magnitude below the methylating potency of N-nitrosomethylurea in rat stomach. The apparent discrepancy to the in vitro data could be due to efficient detoxification processes in mammalian cells.
KW  - Toxikologie
KW  - Nitrosation
KW  - Alkylation
KW  - Amino acids
KW  - DNA binding
Y1  - 1990
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60804
ER  -