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Endogenous mutagens derived from amino acids
1Department of Toxicology, University of Mainz, F.R.G.
Abstract:
L-Cysteine, glutathione and the therapeutically used L-cysteine precursor, N-acetyl-L-cysteine, induced strong mutagenic effects in Salmonella typhimurium (reversion of the his- strains TA97, TA92 and TA104), when tested in the presence of subcellular kidney preparations. The tyrosine metabolites, levodopa (an ortho-hydroquinone) and homogentisic acid (a para-hydroquinone) reverted various his- strains as well. This mutagenicity did not require the presence of mammalian enzymes, and was relatively weak. The induction of gene mutations was also studied in mammalian cells (V79 Chinese hamster cells), using acquisition of resistance toward 6-thioguanine as the marker. L-Cysteine and N-acetyl-L-cysteine were found to be inactive, levodopa was weakly mutagenic, and homogentisic acid was strongly mutagenic (enhancing the mutation frequency 135-fold above background at an exposure concentration of 50 microM). This finding is striking as the urinary concentration of homogentisic acid is about 1000 times higher in patients with a genetic defect in homogentisic acid 1,2-dioxygenase (alkaptonuria). Genotoxic and carcinogenic effects of other amino acids and metabolites, reported in the literature, are discussed as well.
Insights
L-Cysteine and N-acetyl-L-cysteine showed mutagenic effects in bacterial tests. However, in mammalian cells, only homogentisic acid demonstrated significant mutagenicity, particularly in alkaptonuria patients.
Area of Science:
- Biochemistry
- Toxicology
- Genetics
Background:
- L-Cysteine and its precursor N-acetyl-L-cysteine are widely used supplements.
- Tyrosine metabolites like levodopa and homogentisic acid are relevant in metabolic pathways.
- Alkaptonuria is a genetic disorder characterized by elevated homogentisic acid levels.
Purpose of the Study:
- To investigate the mutagenic potential of L-cysteine, glutathione, N-acetyl-L-cysteine, levodopa, and homogentisic acid.
- To compare mutagenicity in bacterial and mammalian cell systems.
- To assess the implications of homogentisic acid's mutagenicity in alkaptonuria.
Main Methods:
- Bacterial mutagenicity assays using Salmonella typhimurium strains (TA97, TA92, TA104) with kidney preparations.
- Mammalian cell gene mutation assays in V79 Chinese hamster cells measuring resistance to 6-thioguanine.
- Comparative analysis of mutagenic effects across different cell systems and compounds.
Main Results:
- L-Cysteine, glutathione, and N-acetyl-L-cysteine induced mutagenicity in Salmonella typhimurium.
- Levodopa and homogentisic acid also showed mutagenic effects in bacteria, though weaker.
- In V79 cells, L-cysteine and N-acetyl-L-cysteine were inactive, levodopa was weakly mutagenic, and homogentisic acid was strongly mutagenic (135-fold increase).
Conclusions:
- Homogentisic acid exhibits significant mutagenic potential in mammalian cells, with implications for alkaptonuria.
- The mutagenicity of these compounds varies significantly between bacterial and mammalian test systems.
- Further research is warranted on the genotoxic effects of amino acids and metabolites.