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Rapid Analysis of Chromosome Aberrations in Mouse B Lymphocytes by PNA-FISH
Published on: August 19, 2014
A comparative analysis of chromosomal aberrations in cultured human lymphocytes due to fluoroquinolone drugs at
M Anupama1, J P Seiler, P B Murthy
1International Institute of Biotechnology and Toxicology, Padappai, Kancheepuram District, Tamil Nadu 601301, India.
Abstract:
Fluoroquinolones (FQ) are broad-spectrum antibacterial agents widely used for the treatment of infections with various types of gram negative and gram positive bacteria. Specifically, gatifloxacin (GFX) is under development as a component in a new antituberculosis fixed-dose drug combination. In the context of this project, GFX was also tested for genotoxic activity in human peripheral lymphocytes, and the induction of chromosomal aberrations by GFX in PHA-M stimulated cultured human lymphocytes, investigated under conditions of conventional and increased expression times, was further compared to the analogous effects induced by some other second- and third-generation FQ antibacterial agents, namely ofloxacin (OFX), ciprofloxacin (CFX) and sparfloxacin (SFX). OFX did not induce any significant chromosomal aberrations in human lymphocytes. CFX and SFX exhibited slight to moderate clastogenic potential at cytotoxic concentrations (150, 175, 200 and 225 microg/ml), and GFX, a third-generation FQ, induced a clear, concentration-dependent increase in the frequency of chromosomal aberrations at cytotoxic concentrations (150, 200 and 250 microg/ml). These effects were not apparent when metaphases were analysed at the conventionally used sampling time of 24 h, but only after prolongation of the expression time between treatment and harvesting to a sampling time of 36 h (4 h exposure and 32 h expression period). Also, an increased incidence of numerical aberrations (polyploidy and endoreduplication) was seen with GFX at non-cytotoxic concentrations (12.5, 25, 50 and 75 microg/ml). These effects can be attributed to the slight cross-reactivity of FQs between their inhibitory activity towards their intended targets, the prokaryotic type II topoisomerase enzymes DNA gyrase and topoisomerase IV, and the analogous mammalian enzyme topoisomerase II. We have also observed the formation of polycentrics, i.e., chromosomes with five to six centromeres, a rarely reported structural aberration, in GFX-treated cells. The significance of these observations with respect to the conventional conduct of such studies and to the interpretation of the effects is discussed.
Insights
Gatifloxacin (GFX), a third-generation fluoroquinolone (FQ), induced chromosomal aberrations in human lymphocytes, particularly at longer expression times. Other FQs like ciprofloxacin and sparfloxacin showed some clastogenic potential, while ofloxacin did not.
Area of Science:
- Pharmacology
- Genetics
- Toxicology
Background:
- Fluoroquinolones (FQ) are broad-spectrum antibiotics.
- Gatifloxacin (GFX) is an FQ under development for tuberculosis treatment.
- Genotoxic potential of FQs in human cells requires investigation.
Purpose of the Study:
- To assess the genotoxic activity of gatifloxacin (GFX) in human lymphocytes.
- To compare the clastogenic effects of GFX with other fluoroquinolones (ofloxacin, ciprofloxacin, sparfloxacin).
- To evaluate the impact of expression time on FQ-induced chromosomal aberrations.
Main Methods:
- Cultured human lymphocytes were treated with various concentrations of GFX, ofloxacin (OFX), ciprofloxacin (CFX), and sparfloxacin (SFX).
- Chromosomal aberrations were analyzed at conventional (24 h) and prolonged (36 h) expression times.
- Numerical and structural aberrations, including polyploidy, endoreduplication, and polycentrics, were quantified.
Main Results:
- GFX induced a concentration-dependent increase in chromosomal aberrations at cytotoxic levels, especially at 36 h expression time.
- CFX and SFX showed slight to moderate clastogenic potential at cytotoxic concentrations.
- OFX did not induce significant chromosomal aberrations; GFX also caused numerical aberrations at non-cytotoxic concentrations.
Conclusions:
- GFX exhibits genotoxic potential, inducing chromosomal aberrations in human lymphocytes, with effects being more pronounced at extended expression times.
- The observed genotoxicity may be linked to FQ cross-reactivity with mammalian topoisomerase II.
- Prolonged expression times are crucial for detecting certain FQ-induced genotoxic effects, impacting study interpretation.
