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Inverse correlation between bacterial frameshift mutagenicity and yeast mitochondrial effects of antitumour
Abstract:
The mutagenicity of a series of derivatives of 9-anilinoacridine, including the clinical antitumour agent amsacrine, has been assessed using a bacterial frameshift tester strain (Salmonella typhimurium TA1537) and a yeast petite colony assay (Saccharomyces cerevisiae 5178B). The results have been compared with microbial mammalian cell cytotoxicity, DNA binding affinity and acridine base strength (pKa). Compounds containing strong electron donor substituents on the acridine ring, and which have a high acridine pKa, show minimal frameshift mutagenicity but are strong inducers of petite yeast mutants. Conversely, some compounds which have a high DNA binding constant but a significant proportion of uncharged form at neutral pH, show high frameshift mutagenicity but minimal induction of petite mutants. It is hypothesised that this inverse relationship arises from the presence of trans-membrane drug transport mechanisms which act to exclude some compounds, particularly strongly basic compounds from the cytoplasm and to concentrate them in mitochondria.
Insights
The mutagenicity of 9-anilinoacridine derivatives varies based on their chemical properties. Some compounds induce petite yeast mutants, while others cause bacterial frameshift mutations, suggesting different cellular mechanisms.
Area of Science:
- Toxicology
- Molecular Biology
- Genetics
Background:
- 9-Anilinoacridine derivatives, including amsacrine, are investigated for their biological activities.
- Understanding their mutagenicity is crucial for assessing potential risks and therapeutic applications.
- Acridine compounds interact with DNA and cellular components, influencing their toxicological profile.
Purpose of the Study:
- To assess the mutagenicity of 9-anilinoacridine derivatives using bacterial and yeast assays.
- To correlate mutagenicity with DNA binding affinity, base strength (pKa), and cytotoxicity.
- To investigate the relationship between chemical structure and mutagenic mechanisms.
Main Methods:
- Bacterial frameshift assay using Salmonella typhimurium TA1537.
- Yeast petite colony assay using Saccharomyces cerevisiae 5178B.
- Measurement of DNA binding affinity, cytotoxicity, and acridine base strength (pKa).
Main Results:
- Compounds with high acridine pKa and electron-donating substituents showed low frameshift mutagenicity but high induction of petite yeast mutants.
- Compounds with high DNA binding affinity and significant uncharged forms at neutral pH exhibited high frameshift mutagenicity and low petite mutant induction.
- An inverse relationship was observed between frameshift mutagenicity and petite mutant induction.
Conclusions:
- The observed inverse relationship in mutagenicity is hypothesized to be due to trans-membrane drug transport mechanisms.
- These mechanisms may exclude basic compounds from the cytoplasm and concentrate them in mitochondria.
- Differential cellular uptake and localization influence the mutagenic outcome of 9-anilinoacridine derivatives.