Comparative genotoxicity of quinolone and quinolonyl-lactam antibacterials in the in vitro micronucleus assay in Chinese hamster ovary cells.
The in vitro micronucleus assay is gaining increased attention as a potential alternative to the standard in vitro metaphase analysis assay. In particular, the in vitro micronucleus assay has been proposed as a useful method for chemicals that induce both structural and numerical chromosome alterations, such as DNA gyrase/topoisomerase inhibitors. In this study, we compared the micronucleus-inducing activity of quinolonyl-lactam antibacterials that inhibit DNA-gyrase and bind to penicillin-binding proteins relative to the activity of structurally related quinolone antibacterials that also inhibit DNA-gyrase. All of the quinolones that were structurally related to the quinolonyl-lactams were cytotoxic and induced large increases in the frequency of micronucleated binucleated cells (MNBC) at concentrations between 0.02 and 0.16 mM. These changes were larger than those seen with the commercial quinolones, ciprofloxacin (cytotoxic at > or = 0.57 mM and MNBC at > or = 0.3 mM) and nalidixic acid (cytotoxic at 1.8 mM and no MNBC up to this dose). In contrast, the quinolonyl-lactams were not cytotoxic up to 1.0 mM concentrations and induced either no MNBC or a low frequency of MNBC at higher concentrations compared to the quinolones. Quinolonyl-lactams appear to be less cytotoxic and genotoxic than structurally related quinolones. These results add to the growing database on the in vitro micronucleus assay in general, and more specifically to the relatively small database for the in vitro micronucleus assay in Chinese hamster ovary cells.
Gibson
D P
DP
Miami Valley Laboratories, The Procter & Gamble Company, Cincinnati, Ohio 45253-8707, USA. gibson.dp@pg.com
Ma
X
X
Switzer
A G
AG
Murphy
V A
VA
Aardema
M J
MJ
D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity*; D016466:CHO Cells; D002939:Ciprofloxacin / Q000633:toxicity; D006224:Cricetinae; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D009268:Nalidixic Acid / Q000633:toxicity; D059005:Topoisomerase II Inhibitors
D000890:Anti-Infective Agents; D009153:Mutagens; D059005:Topoisomerase II Inhibitors; D009268:Nalidixic Acid; D002939:Ciprofloxacin