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The Salmonella/mammalian microsome mutagenicity test: comparison of human and rat livers as activating systems
Abstract:
The mutagenicity of several test compounds was verified by the Salmonella/microsome mutagenicity test (Ames test), using both human liver and rat liver (untreated or pretreated with Aroclor 1254) S9 under identical experimental conditions. Aflatoxin B1, 3-methylcholanthrene, and cigarette-smoke condensate were less mutagenic in the presence of human-liver S9 than in the presence of rat-liver S9 (particularly after treatment with Aroclor 1254). The opposite was observed with 2-aminonanthracene and to a lesser degree with 2-aminofluorene; correlation studies indicate that the two compounds were activated by the same or by very similar enzymes, probably cytochrome P-450s. These results clearly indicate that human-liver S9, as an activating system, behaves differently than rat-liver S9; therefore, it may constitute a useful, additional tool for the study of mutagenicity and probably, carcinogenicity in man.
Insights
Human liver S9 enzymes activate mutagens differently than rat liver S9 enzymes. This finding suggests human liver S9 is a valuable tool for studying mutagenicity and carcinogenicity in humans.
Area of Science:
- Toxicology
- Biochemistry
- Genetics
Background:
- The Salmonella/microsome mutagenicity test (Ames test) is a standard assay for detecting mutagenic compounds.
- Metabolic activation by liver enzymes (S9 fraction) is crucial for assessing the mutagenicity of many chemicals.
- Differences in enzyme activity between species can affect mutagenicity test outcomes.
Purpose of the Study:
- To compare the mutagenic activation capabilities of human liver S9 and rat liver S9.
- To investigate the differential metabolic activation of various test compounds by human and rat liver S9.
- To evaluate the utility of human liver S9 as an alternative to rat liver S9 in mutagenicity testing.
Main Methods:
- Utilized the Salmonella/microsome mutagenicity test (Ames test).
- Employed human liver S9 and rat liver S9 (untreated and Aroclor 1254-pretreated) under identical conditions.
- Tested mutagenicity of aflatoxin B1, 3-methylcholanthrene, cigarette-smoke condensate, 2-aminonanthracene, and 2-aminofluorene.
Main Results:
- Aflatoxin B1, 3-methylcholanthrene, and cigarette-smoke condensate showed lower mutagenicity with human liver S9 compared to rat liver S9 (especially Aroclor 1254-treated).
- 2-aminonanthracene and 2-aminofluorene exhibited higher mutagenicity with human liver S9.
- Correlation studies suggested activation by similar cytochrome P-450 enzymes for 2-aminonanthracene and 2-aminofluorene.
Conclusions:
- Human liver S9 demonstrates distinct metabolic activation patterns compared to rat liver S9.
- Human liver S9 is a potentially valuable tool for assessing mutagenicity and carcinogenicity relevant to humans.
- Species-specific differences in metabolic activation are critical for accurate risk assessment.