Abstract
Ofloxacin, a specific inhibitor of bacterial topoisomerase II, is known to inhibit the growth of yeast cells and to induce rho −mutants in the yeast S. cerevisiae. The frequency of ofloxacin-induced petite mutants under non-growth conditions was found to be strongly diminished when the cells were depleted in intramitochondrial ATP. Under optimal conditions of mitochondrial mutagenesis the drug induced mitotic recombination and reverse mutation in diploid strains but failed to cure either killer plasmids or the 2 μm DNA of dividing cells. The sensitivity to ofloxacin of the strains deficient in the DNA strandbreak repair pathway (rad52) was significantly higher then that of the wild-type strains and of the mutants deficient in excision or mutagenic DNA repair. The results are compatible with the idea that the cytotoxic and genetic activity of ofloxacin in yeast probably results from the inhibited DNA ligation function of topoisomerase II creating DNA breaks that are reparable through the recombination repair pathway.
This is a preview of subscription content, log in via an institution to check access.
References
Castora FJ, Simpson MV (1979) Search for a DNA gyrase in mammalian mitochondria. J Biol Chem 254:11193–11195
Castora FJ, Lazarus M, Kunes D (1985) The presence of mitochondrial-DNA topoisomerases in human acute-leukemia cells. Biochem Biophys Res Commun 130:854–866
Ciaravino V, Suto MJ, Theiss JC (1993) High capacity in-vitro micronucleus assay for assessment of chromosome damage: results with quinolone/naphthyridone antibacterials. Mutat Res 298: 227–236
Clerch B, Barbé J, Llagostera M (1992) The role of the excision and error-prone repair systems in mutagenesis by fluorinated quinolones in Salmonella typhimurium. Mutat Res 281:207–213
DeMarini DM, Lawrence BK (1992) Prophage induction by DNA topoisomerase II poisons and reactive-oxygen species: role of DNA breaks. Mutat Res 267:1–17
Ebringer L, Šubík J, Lahitová N, Trubačík S, Horváthová R, Siekel P, Krajčovič J (1982) Mutagenic effects of two nitrofuran food preservatives. Neoplasma 29:675–683
Friedberg EC (1988) Deoxyribonucleic acid repair in the yeast Saccharomyces cerevisiae. Microbiol Rev 52:70–102
Fu KP, Grace ME, Hsiao CL, Hung PP (1988) Elimination of antibiotic-resistant plasmids by quinolone. Chemotherapy 34: 415–418
Gbelská Y, Šubík J, Svoboda A, Goffeau A, Kováč L (1983) Intramitochondrial ATP and cell functions: yeast cells depleted of intramitochondrial ATP lose the ability to grow and multiply. Eur J Biochem 130:281–286
Goecke E (1991) Mechanism of quinolone mutagenity in bacteria. Mutat Res 248:135–143
Jannatipour M, Lin YX, Nitiss JL (1993) The top2–5 mutant of yeast topoisomerase II encodes an enzyme resistant to etoposide and amsacrine. J Biol Chem 268:18586–18592
Krajčovič J, Ebringer L, Polónyi J (1989) Quinolones and coumarins eliminate chloroplasts from Euglena gracilis. Antimicrob Agents Chemother 33:1883–1889
Mamber SW, Kolek B, Brookshire KW, Bonner DP, Fung-Tomc J (1993) Activity of quinolones in the Ames Salmonella TA102 mutagenicity test and other bacterial genotoxicity assays. Antimicrob Agents Chemother 37:213–217
Moreau NJ, Robaux H, Baron L, Tabary X (1990) Inhibitory effects of quinolones on pro-and eucaryotic DNA topoisomerases I and II. Antimicrob Agents Chemother 34:1955–1960
Nitiss JL, Lin YX, Hsiung Y (1993) A temperature-sensitive topoisomerase-II allele confers temperature-dependent drug-resistance on amsacrine and etoposide—a genetic system for determining the targets of topoisomerase-II inhibitors. Cancer Res 53:89–93
Ogur M, St John R, Nagai S (1957) Tetrazolium overlay technique for population studies of respiration deficiency in yeast. Science 125:98–99
Obernauerová M, Šubík J, Ebringer L (1992) Ofloxacin induces cytoplasmic respiration-deficient mutants in the yeast Saccharomyces cerevisiae. Curr Genet 21:443–446
Osheroff N, Zechiedrich EL, Gale KC (1991) Catalytic function of DNA topoisomerase II. Bio Essays 13:269–275
Prakash SL, Prakash L, Burke W, Montelone BA (1980) Effect of the rad52 gene on recombination in Saccharomyces cerevisiae. Genetics 94:31–50
Resnick MA, Martin P (1976) The repair of double-strand breaks in nuclear DNA of Saccharomyces cerevisiae and its genetic control. Mol Gen Genet 143:119–129
Sulo P, Michalčáková S, Reiser V (1992) Construction and properties of K1-type killer wine yeast. Biotechnol Lett 14:55–60
Šubík J, Takácsová G, Kováč L (1978) Intramitochondrial ATP and cell function. I. Growing yeast cells depleted of intramitochondrial ATP are losing mitochondrial genes. Mol Gen Genet 166:103–116
Wang JC (1985) DNA topoisomerases. Annu Rev Biochem 54: 665–697
Wang JC (1987) Recent studies of DNA topoisomerases. Biochim Biophys Acta 909:1–9
Wolfson JS, Hooper DC (1985) The fluoroquinolones: structures, mechanisms of action and resistance, and spectra of activity in vitro. Antimicrob Agents Chemother 28:581–586
Zimmermann FK, Kern R, Rasenberger H (1975) A yeast strain for the simultaneous detection of induced mitotic crossing-over, mitotic gene conversion and reverse mutation. Mutat Res 28: 381–388
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Obernauerová, M., Ŝubík, J. Energy-dependent mitochondrial mutagenicity of antibacterial ofloxacin and its recombinogenic activity in yeast. Curr Genet 26, 281–284 (1994). https://doi.org/10.1007/BF00309561
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00309561