Cytotechnology

, Volume 64, Issue 4, pp 443–449 | Cite as

In vitro genotoxic perspective of Tamiflu

Original Research

Abstract

The aim of this study was to investigate the genotoxic and/or cytotoxic effects of Tamiflu, commercial form of the oseltamivir antiviral and most frequently prescribed for the treatment of influenza infections, on cultured human peripheral lymphocytes by using sister chromatid exchange (SCE), chromosomal aberration (CA), and cytokinesis-blocked micronucleus (CBMN) assays. Cells were treated with 0.5, 1, 2 μg/mL oseltamivir, the Tamiflu capsule ingredient, for 24 or 48 h in the absence or presence of an exogenous metabolic activation system (S9 mix). The test chemical did not demonstrate any genotoxic effect dose-dependently but it showed a weak cytotoxicity on cells in this study. On the other hand, some concentrations of Tamiflu (2 μg/mL without S9 mix for 48 h and 1 μg/mL with S9 mix) induced SCE and also decreased significantly the proliferation index (PI) (48 h period) and the nuclear division index (NDI) (24 h period) (P < 0.05) in the absence of S9 mix. Considering the results, Tamiflu did not induce significant increases of CA or micronucleated cells in vitro in cultured peripheral blood lymphocytes under the treatment conditions used but weak SCE induction was observed. On the other hand, the weak cytotoxic effects observed disappeared in the cultures treated in presence of the S9 mix.

Keywords

Tamiflu Oseltamivir In vitro human lymphocytes Sister chromatid exchange Micronuclei Cytotoxicity 

Notes

Acknowledgments

This study was funded by Çukurova University Research Fund; FEF2008YL3.

References

  1. Albertini RJ, Anderson D, Douglas GR, Hagmar L, Hemminki K, Merlo F, Natarajan AT, Norppa H, Shuker DE, Tice R, Waters MD, Aitio A (2000) IPCS Guidelines for the Monitoring of Genotoxic Effects of Carcinogens in Humans. Mutat Res 463:111–172CrossRefGoogle Scholar
  2. EMEA (European Medicines Agency) (2009) Press release, European Medicines Agency gives guidance for use of antiviral medicines in case of a novel influenza A/H1N1 pandemic. Doc. Ref. EMEA/285148Google Scholar
  3. Evans HJ (1984) Human peripheral blood lymphocytes for the analysis of chromosome aberrations in mutagen tests. In: Kilbey BJ, Legator M, Nichols W et al (eds) Handbook of mutagenicity test procedures, 2nd edn. Elsevier Sci BV, Amsterdam, pp 405–427Google Scholar
  4. Fenech M (2000) The in vitro micronucleus technique. Mutatat Res 455:81–95CrossRefGoogle Scholar
  5. Freund B, Gravenstein S, Elliott M, Miller I (1999) Zanamivir: a review of clinical safety. Drug Saf 21:267–281CrossRefGoogle Scholar
  6. Gelboin HV, Wortham JS, Wilson RG (1967) 3-methylcholanthrene and phenobarbital stimulation of rat liver RNA polymerase. Nature 214:281–283. doi: 10.1038/214281a0 CrossRefGoogle Scholar
  7. Latt SA (1974) Sister chromatid exchanges, indices of human chromosome damage and repair: detection by fluorescence and induction by mitomycin-C. Proc Natl Acad Sci USA 71:3162–3166CrossRefGoogle Scholar
  8. Mace ML Jr, Daskal Y, Wray W (1978) Scanning electron microscopy of chromosome aberrations. Mutat Res 52:199–206CrossRefGoogle Scholar
  9. Maron DM, Ames BN (1983) Revised method for the Salmonella mutagenicity test. Mutat Res 113:173–215CrossRefGoogle Scholar
  10. Perry P, Evans HJ (1975) Cytological detection of mutagen-carcinogen exposure by sister chromatid exchange. Nature 258:121–125CrossRefGoogle Scholar
  11. Perry PE, Thompson EJ (1984) The methodology of sister chromatid exchanges. In: Kilbey BJ, Legator M, Nichols W et al (eds) Handbook of Mutagenicity Test Procedures, 2nd edn. Elsevier Sci, Amsterdam, pp 495–529Google Scholar
  12. Ribas G, Xamena N, Creus A, Marcos R (1996) Sister-chromatid exchanges (SCE) induction by inhibitors of DNA topoisomerases in cultured human lymphocytes. Mutat Res 368:205–211CrossRefGoogle Scholar
  13. Rothfuss A, Schütz P, Bochum S, Volm T, Eberhardt E, Kreienberg R, Vogel W, Speit G (2000) Induced micronucleus frequencies in peripheral lymphocytes as a screening test or carriers of a BRCA1 mutation in breast cancer families. Cancer Res 60:390–394Google Scholar
  14. Speit G, Haupter S (1985) On the mechanisms of differential Giemsa staining of bromodeoxyuridine-substituted chromosomes. II. Differences between the demonstration of sister chromatid differentiation and replication patterns. Hum Genet 70:126–129CrossRefGoogle Scholar
  15. Ueng YF, Ko HC, Chen CF, Wang JJ, Chen KT (2002) Modulation of drug-metabolizing enzymes by extracts of a herbal medicine Evodia rutaecarpa in C57BL/6 J mice. Life Sci 71:1267–1277. doi: 10.1016/S0024-3205(02)01854-4 CrossRefGoogle Scholar
  16. Ustaçelebi Ş, Abacıoğlu H, Badur S (2004) Moleküler, Klinik ve Tanısal Viroloji (Molecular, clinic and diagnostic virology). Güneş Kitabevi, AnkaraGoogle Scholar
  17. Ward JF, Samson LD, Alt FW, Petrini JHJ, Elledge SJ, Jackson SP, Kolodner RD, Weinert T, Yanagida M, Carr AM, Weiss RS, Hengartner MO (2000) Genome stability and checkpoint control. In: Proceedings of 2000 symposium. Biological responses to DNA damage. Cold spring harbor symposia on quantitative biology LXVGoogle Scholar
  18. Winquist AG, Fukuda K, Bridges CB, Cox NJ (1999) Neuraminidase inhibitors for treatment of influenza A and B infections. MMWR Morb Mortal Wkly Rep 48:1–9Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  1. 1.Department of Biology, Faculty of Science and LettersCukurova UniversityAdanaTurkey

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