High capacity in vitro micronucleus assay for assessment of chromosome damage: results with quinolone/naphthyridone antibacterials.
A high capacity in vitro micronucleus assay was developed to evaluate the ability of selected 6-fluorinated quinolone and naphthyridone antibacterial compounds to induce micronuclei (MN) in vitro in V79 Chinese hamster lung cells. Log-phase cells in six-well cluster dishes were exposed for 3 h in the absence of S9 to 34 compounds. After treatment, cells were refed with media containing cytochalasin B, incubated for 16 h, and harvested for cell-cycle kinetics (CCK) and MN analyses. The quinolones tested were grouped according to the substituent at the 8-position. All 4 compounds having a halogen substitution at position 8, five of the six 8-trifluoromethyl quinolones, and all eight 8-methoxy-substituted compounds induced a significant increase in MN. Only 5 of the 10 naphthyridone compounds tested, having a variety of substituents at the 7-position, were inducers of MN and the overall magnitude of the response was less than with the quinolones. The minimum clastogenic concentration for the quinolones ranged from 4 to 400 micrograms/ml and for the naphthyridones this range was from 22.5 to 100 micrograms/ml. In the groups examined, napthyridone compounds were less likely than quinolones to induce in vitro MN, particularly when the substituent at the 7-position in the naphthyridone contains some bulk (methyl groups) around the amine side-chain. Most of the quinolones tested induced MN, irrespective of the substituents at positions 7 or 8.
Ciaravino
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Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Suto
M J
MJ
Theiss
J C
JC
D042462:4-Quinolones; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D006224:Cricetinae; D003412:Cricetulus; D006846:Hydrocarbons, Halogenated / Q000737:chemistry / Q000633:toxicity; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D009287:Naphthyridines / Q000737:chemistry / Q000633:toxicity*; D013329:Structure-Activity Relationship
D042462:4-Quinolones; D000890:Anti-Infective Agents; D006846:Hydrocarbons, Halogenated; D009153:Mutagens; D009287:Naphthyridines