A comparative analysis of chromosomal aberrations in cultured human lymphocytes due to fluoroquinolone drugs at different expression periods

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 μg/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 μg/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 μg/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.

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Fig. 1

Abbreviations

GFX:

Gatifloxacin

CFX:

Ciprofloxacin

OFX:

Ofloxacin

SFX:

Sparfloxacin

FQ:

Fluoroquinolone

MMC:

Mitomycin C

BrdU:

5-bromo-2-deoxyuridine

DMSO:

Dimethylsulphoxide

FBS:

Foetal bovine serum

PHA-M:

Phytohaemagglutinin

MI:

Mitotic index

RI:

Replicative index

SCE:

Sister chromatid exchange

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Correspondence to J. P. Seiler.

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Anupama, M., Seiler, J.P. & Murthy, P.B. A comparative analysis of chromosomal aberrations in cultured human lymphocytes due to fluoroquinolone drugs at different expression periods. Arch Toxicol 84, 411–420 (2010). https://doi.org/10.1007/s00204-009-0509-9

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Keywords

  • Gatifloxacin
  • Ciprofloxacin
  • Ofloxacin
  • Sparfloxacin
  • Chromosomal aberration
  • Human lymphocyte