Genotoxicity of 17 gyrase- and four mammalian topoisomerase II-poisons in prokaryotic and eukaryotic test systems.
The genotoxic potency of certain classes of topoisomerase II poisons is correlated with their affinity to the topoisomerase protein rather than with the presence of 'classical' structural alerts for DNA reactivity: bacterial topoisomerase II poisons (specifically named gyrase inhibitors) are highly genotoxic in prokaryotic systems; mammalian topoisomerase II poisons are potent mutagens/clastogens in eukaryotic systems. Studies with bacterial, lower eukaryotic and mammalian genotoxicity tests were performed to draw structure-activity conclusions and address risk-benefit considerations for the class of quinolone gyrase inhibitors. All 17 gyrase inhibitors investigated in this study showed genotoxic activity in Salmonella typhimurium strain TA102 and the SOS test. The genotoxic and the toxic activities increased in a highly parallel fashion from the parent compounds, nalidixic acid and oxolinic acid, to the new generation fluoroquinolones. Generally, the most potent fluoroquinolones also show clear-cut positive effects in eukaryotic test systems, although at concentrations 100-1000-fold higher than those effective in bacteria and also 100-1000-fold higher than the minimal genotoxic concentrations of antitumour topoisomerase II inhibitors (ellipticine, teniposide, mAMSA) used as reference compounds. However, subtle structural modifications of the quinolones can strongly diminish the preferential genotoxicity in the prokaryotic test systems.
D000818:Animals; D001711:Biotransformation; D016466:CHO Cells; D002460:Cell Line; D002869:Chromosome Aberrations; D006224:Cricetinae; D003412:Cricetulus; D004260:DNA Repair; D004791:Enzyme Inhibitors / Q000633:toxicity*; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D005057:Eukaryotic Cells; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008223:Lymphoma; D051379:Mice; D015162:Micronucleus Tests; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D016296:Mutagenesis; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D011387:Prokaryotic Cells; D015363:Quinolones / Q000633:toxicity; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000254:growth & development; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D009153:Mutagens; D015363:Quinolones; D059005:Topoisomerase II Inhibitors; D007041:Hypoxanthine Phosphoribosyltransferase