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Mutagenicity of quinolone antibacterials
1Department of Toxicology, Abbott Laboratories, Abbott Park, Illinois.
Drug Safety
|May 1, 1992
Summary
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.