In vitro induction of micronuclei and chromosome aberrations by quinolones: possible mechanisms.
The bacterial gyrase inhibitors, ciprofloxacin and PD 124816, were tested for clastogenic and aneugenic activity in V79 Chinese hamster lung cells in vitro. Cells were exposed for 3 h, washed free of drug, and subcultured for assessment of various endpoints. For structural chromosomal aberration (SCA) analysis, cells were incubated for 18 h, and treated with Colcemid for 2 h before harvest. For micronucleus (MN) analysis, treated cells were incubated with cytochalasin B (CYB) for 16 h. Aneugenicity was assessed by utilizing antikinetochore antibody to detect kinetochore-containing (K +) MN. Both quinolones induced significant increases in SCAs and MN, indicating clastogenic activity. With both compounds, however, the MN response was apparent at lower doses, and remained much higher throughout the dose range than the SCA response. The induced MN were predominantly K --, indicating that aneugenicity was not playing a major role in their induction. A possible explanation for the chromosome effects is that cross-reactivity of the gyrase inhibitors with mammalian topoisomerase II interferes with the separation of chromatids at anaphase leading to chromosome breaks and MN. Quinolones are known to inhibit resolution of the normally transient topoisomerase II-DNA cleavable complex, which may result in chromosome stickness. Thus, SCAs detected in metaphase cells may be attributed to quinolone-induced inhibition of topoisomerase II prior to mitosis while MN arise in binucleated cells as a result of this effect which interferes with chromatid separation during anaphase.
Curry
P T
PT
Microbiological Associates, Inc., Rockville, MD 20850, USA.
Kropko
M L
ML
Garvin
J R
JR
Fiedler
R D
RD
Theiss
J C
JC
D000818:Animals; D000890:Anti-Infective Agents; D002453:Cell Cycle; D002470:Cell Survival; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D002939:Ciprofloxacin / Q000633:toxicity*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects; D024841:Fluoroquinolones; D018386:Kinetochores / Q000187:drug effects; D008168:Lung / Q000166:cytology; D048629:Micronuclei, Chromosome-Defective; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D015363:Quinolones / Q000633:toxicity*
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D009153:Mutagens; D015363:Quinolones; C059082:PD 124816; D002939:Ciprofloxacin