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Mutagenicity of quinolone antibacterials
1Department of Toxicology, Abbott Laboratories, Abbott Park, Illinois.
Abstract:
The literature is summarised on the activity of quinolone antibacterial compounds in assays which are commonly used for risk assessment of new pharmaceuticals. These include assays for DNA damage, sister chromatid exchanges, chromosome aberrations and mutation induction. The general pattern of activity exhibited by these compounds is induction of DNA damage in both prokaryotic and eukaryotic cells, and induction of mutations in DNA repair-proficient bacteria and at the thymidine kinase locus in mammalian cells. They do not appear as a class to induce mutations at the hypoxanthine-guanine-phosphoribosyltransferase (HGPRT) or Na+,K(+)-ATPase loci or to cause chromosome aberrations. It is suggested that these actions may be the result of interference with eukaryotic topoisomerase and that this interference differs in some respects from the topoisomerase interference caused by certain antitumour compounds. The postulated mechanism of action has important implications for assessment of risk from consumption of quinolone antibacterials. The risk of adverse genotoxic events should vary directly with the concentration of drug reaching the intracellular enzyme target and the affinity of the drug for the target. Results of carcinogenicity studies conducted to date with the quinolone antibacterials suggest minimal risk from long term consumption of the newer, second-generation compounds.
Insights
Quinolone antibacterials can cause DNA damage and mutations in cells. However, newer quinolones pose minimal long-term risks due to their specific interactions with cellular targets.
Area of Science:
- Pharmacology
- Toxicology
- Molecular Biology
Background:
- Quinolone antibacterials are widely used pharmaceuticals.
- Risk assessment for pharmaceuticals commonly involves genotoxicity assays.
- Understanding the genotoxic profile of quinolones is crucial for patient safety.
Purpose of the Study:
- To summarize the genotoxic activity of quinolone antibacterial compounds.
- To evaluate their effects in standard pharmaceutical risk assessment assays.
- To elucidate the mechanism of action and its implications for risk assessment.
Main Methods:
- Literature review of quinolone activity in genotoxicity assays.
- Analysis of data on DNA damage, sister chromatid exchanges, chromosome aberrations, and mutation induction.
- Comparison with known mechanisms of antitumour compounds targeting topoisomerase.
Main Results:
- Quinolones generally induce DNA damage in prokaryotic and eukaryotic cells.
- Mutations are induced in DNA repair-proficient bacteria and at the thymidine kinase locus in mammalian cells.
- Quinolones do not typically cause mutations at HGPRT or Na+,K(+)-ATPase loci or induce chromosome aberrations.
Conclusions:
- The genotoxic effects of quinolones may stem from interference with eukaryotic topoisomerase.
- Risk assessment should consider drug concentration and affinity for the intracellular target.
- Newer, second-generation quinolones show minimal carcinogenic risk in long-term studies.