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Evaluation of 4-methylimidazole, in the Ames/Salmonella test using induced rodent liver and lung S9
Carol Beevers1, Richard H Adamson2
1Department of Genetic and Molecular Toxicology, Covance Laboratories, Ltd, North Yorkshire, HG3 1PY, United Kingdom.
Abstract:
4-methylimidazole (4-MeI) is formed by the interaction of ammonia with reducing sugars and low levels have been identified as a by-product in coffee, soy sauce, wine, dark beers, soft drinks, and caramel colors. The 4-MeI has been reported to induce alveolar/bronchiolar tumors in mice but not rats. Its mechanism of action is unlikely to be due to genotoxicity as 4-MeI does not induce mutation in Salmonella typhimurium and does not induce micronuclei in rodent peripheral erythrocytes or bone marrow cells. However, the question of whether genetically reactive intermediates could be formed via lung-specific metabolism has not previously been addressed. The 4-MeI was tested for its ability to induce mutation in five standard Ames strains of S. typhimurium using induced rat (F344/N) and mouse (B6C3F1) liver and lung S9 as a source of exogenous metabolism. The chemicals were tested in an OECD 471-compliant bacterial reverse mutation assay, using both plate-incorporation and pre-incubation methodologies, together with 10% S-9 metabolic activation. No induction of mutation (as measured by an increase in revertant colonies) was observed and it was concluded that 4-MeI was not mutagenic in S. typhimurium using either rodent liver or lung S9 for exogenous metabolism.
Insights
4-methylimidazole (4-MeI), found in various foods, did not show mutagenic potential in bacterial tests. This study investigated its genotoxicity using liver and lung enzymes, finding no evidence of mutation induction.
Area of Science:
- Toxicology
- Food Chemistry
- Genetics
Background:
- 4-methylimidazole (4-MeI) is a common food by-product formed during heating processes.
- While 4-MeI has induced tumors in mice, its genotoxic mechanism remains unclear.
- Previous studies did not investigate lung-specific metabolism of 4-MeI.
Purpose of the Study:
- To assess the mutagenicity of 4-methylimidazole (4-MeI) using the Ames test.
- To determine if lung-specific metabolism influences 4-MeI's genotoxic potential.
- To evaluate 4-MeI's mutagenicity with and without exogenous metabolic activation from rodent liver and lung enzymes.
Main Methods:
- The bacterial reverse mutation assay (OECD 471) was employed using five standard Salmonella typhimurium strains.
- 4-MeI was tested with and without induced rat and mouse liver and lung S9 fractions for metabolic activation.
- Both plate-incorporation and pre-incubation methods were utilized with 10% S9 metabolic activation.
Main Results:
- 4-methylimidazole (4-MeI) did not induce mutations in any of the tested Salmonella typhimurium strains.
- No increase in revertant colonies was observed, even when using rodent liver or lung S9 fractions.
- These results indicate a lack of mutagenicity under the tested conditions.
Conclusions:
- 4-methylimidazole (4-MeI) is not mutagenic in Salmonella typhimurium, irrespective of rodent liver or lung metabolic activation.
- The study suggests that genotoxicity is unlikely to be the mechanism behind 4-MeI's tumor induction in mice.
- Further research may be needed to explore alternative mechanisms for 4-MeI's observed carcinogenicity.
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