Tryptophan mutagens

The amino acids L-leucine, T-phenylalanine, L-tyrosine, and L-tryptophan all taste bitter, whereas their D-enantiomers taste sweet (5) (see Amino ACIDS). D-Penicillamine [52-67-5] a chelating agent used to remove heavy metals from the body, is a relatively nontoxic dmg effective in the treatment of rheumatoid arthritis, but T.-penicillamine [1113-41 -3] produces optic atrophy and subsequent blindness (6). T.-Penicillamine is roughly eight times more mutagenic than its enantiomer. Such enantioselective mutagenicity is likely due to differences in renal metaboHsm (7). (R)-ThaHdomide (3) is a sedative—hypnotic (3)-thaHdomide (4) is a teratogen (8). 

This test will also demonstrate excess growth, which may indicate the presence of histidine or tryptophan or their precursors in the test material, which could make testing for mutagenicity impracticable by this method. 

The 3-amino-1 -mcthyl-5//-pyrido[4,3-b]indolc derivatives (31 Trp-P-1) and (32 Trp-P-2) were found as tryptophane pyrolysates in broiled fish and meat and in pyrolysates of protein and amino acids by Sugimura and coworkers198. These mutagens are heterocyclic amines and exhibit mutagenicity in the Ames test supplemented with S-9 mix198. The pyridoindole derivatives Trp-P-1 and Trp-P-2 are /V-hydroxylated at the exocyclic amino group to form proximate reactive compounds. 

Presently about 20 different mutagenic and/or carcinogenic heterocyclic amines (HAs) have been isolated from various heat-processed foods. One class of these HAs is formed by pyrolysis of proteins or some amino acids. These HAs are amino-carbolines (Figure 13.7), and have been identified in grilled, broiled, baked, and fried meat and fish products, in meat sauces and bouillons, as well as in pyrolyzed proteins, glutamate, lysine, phenylalanine, tryptophan, ornithine, and creatine. 

Kada, T., K. Morita, and T. Inoue. Anti-mutagenic action of vegetable factor(s) on the mutagenic principle of tryptophan pyrolysate. Mutat Res 1978 53 351-353. 

Arimoto, S., Nakano, N., Ohara, Y, Tanaka, K. Hayatsu, H. (1982) A solvent effect on the mutagenicity of tryptophan-pyrolysate mutagens in the SalmonellalraarwaaMan microsome assay. Mutat. Res., 102, 105-112... 

The most potent precursors of mutagenicity were methionine, tyrosine, phenylalanine, and the group of heterocyclic amino acids. Tryptophan, histidine, proline, and hydroxyproline were subsequently chlorinated individually. Of these four, tryptophan and proline were the most significant precursors of mutagenic activity, although some activity was also observed in the extract of chlorinated histidine. 

Chlorination of individual amino acids showed that methionine, tyrosine, phenylalanine, tryptophan, and proline produce highly mutagenic extracts. GC-MS analysis of these extracts indicated the presence of only one known mutagen, dichloroacetonitrile, but this mutagen was not present at a level that would be likely to account for the mutagenic activity. 

Matsukura, H. Kawachi, T. Horino, K. Ohgaki, H. Sugimura, T. Takayama, S. Carcinogenicity in mice of mutagenic compounds from a tryptophan pyrolyzate. 

Although not as frequently, several strains of Escherichia coli also are used in genotoxicity testing. E. coli WP2 and its derivatives possess a base-pair substitution in a tryptophan gene.144 Reversion to tryptophan independence can be caused by base-pair substitution mutagens and even some frameshift mutagens. DNA-repair mutations and the pkMIOl plasmid have been introduced into WP2 strains to increase sensitivity. 

Since Amadori compounds are secondary amines, the question of the formation and reactivity of /V-nitroso derivatives arises. Accordingly, Pool el al 22 tested those derived from glucose with Ala, Asp, Phe, Gly, Ser, and Try in five strains of S. typhimurium with and without S9. The first three compounds were not mutagenic, the next two showed low but reproducible increases in the number of his+ revertants in TA1535 (without S9), but the last, containing indolyl-nitrosamine-D-fructose-L-tryptophan, was mutagenic in all five strains, with and without S9. When separated, the Try compound was mutagenic in three strains, without S9. 

T. Sugimura, T. Kawachi, M. Nagao, T. Yahagi, Y. Seino, T. Okamoto, K. Shudo, T. Kosuge, K. Tsuji, K. Wakabayashi, Y. Iitaka, and A. Itai, Mutagenic principle(s) in tryptophan and phenylalanine pyrolysis products, Proc. Japan Acad., 1977, 53, 58-61. 

The title compound, 3-amino[4-14C]harman, 211, found to have synergistic and co-mutagenic effects in bacterial mutation211, has been synthesized212 in seven steps starting from DL-[methylene-14C]tryptophan, 212, and acetaldehyde (equation 85). 

DNA) (al-A R, L-type Ca2+ CH, DNA, 5HT2-R) [co-mutagenic, convulsant, cytoxic, genotoxic, motor depressant, DNA intercalator, sheep Tribulus staggers , vasorelaxant] from pyrolysate of Tryptophan (cooked food)... 

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