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Genotoxic effects of tacrolimus on human lymphocyte cells

  • Human Genetics
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Abstract

We designed in vitro study to determine possible genotoxic effects of tacrolimus (FK-506), which is used as a potent immunosuppressive drug, by using sister chromatid exchange (SCEs), chromosome aberration (CAs), micronuclei tests (MN) and cell growth kinetics such as mitotic index (MI) and replication index (RI) in human lymphocytes. The ceils were treated with 5, 25, 50, and 100 ng/ml concentrations of tacrolimus, for 24 and 48 h treatment periods. Tacrolimus induced CA and MN frequency at all concentrations for 24 and 48 h. In additon, it induced the SCE at the highest concentration for 24 h and at 25 and 100 ng/ml for 48 h. Tacrolimus decreased MI at all concentrations (except 5 ng/ml) for all treatment periods. It also inhibited the RI at 50 and 100 ng/ml concentrations for 24 h and at all concentrations for 48 h. Treatments given with tacrolimus result in the enhance of the different endpoints of genotoxicity, suggesting its mutagenic action on lymphocytes in vitro.

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References

  1. Hiraoka, A., Ohashi, Y., Okamoto, S., et al., Japanese FK506 BMT (Bone Marrow Transplantation) Study Group: Phase III Study Comparing Tacrolimus (FK506) with Cyclosporine for Graft-versus-Host Disease Prophylaxis after Allogeneic Bone Marrow Transplantation, Bone Marrow Transplant., 2001, vol. 28, no. 2, pp.181–185.

    Article  PubMed  CAS  Google Scholar 

  2. Niwa, Y., Terashima, T., and Sumi, H., Topical Application of the Immunosuppressant Tacrolimus Accelerates Carcinogenesis in Mouse Skin, Br. J. Dermatol., 2003, vol. 149, no. 5, pp. 960–967.

    Article  PubMed  CAS  Google Scholar 

  3. Choi, S.J., You, H.S., and Chung, S.Y., Tacrolimus-Induced Apoptotic Signal Transduction Pathway, Transplant. Proc., 2008, vol. 40, no. 8, pp. 2734–2736.

    Article  PubMed  CAS  Google Scholar 

  4. Sommerer, C., Giese, T., Meuer, S., and Zeier, M., New Concepts to Individualize Calcineurin Inhibitor Therapy in Renal Allograft Recipients, Saudi J. Kidney Dis. Transplant., 2010, vol. 21, no. 6, pp. 1030–1037.

    Google Scholar 

  5. Li, H., Rao, A., and Hogan, P.G., Interaction of Calcineurin with Substrates and Targeting Proteins, Trends Cell Biol., 2011, vol. 21, no. 2, pp. 91–103.

    Article  PubMed  CAS  Google Scholar 

  6. Suzuki, T., Ikezumi, Y., Okubo, S., et al., Epstein-Barr Virus DNA Load and Seroconversion in Pediatric Renal Transplantation with Tacrolimus Immunosuppression, Pediatr. Transplant., 2007, vol. 11, no. 7, pp. 749–754.

    Article  PubMed  CAS  Google Scholar 

  7. Rauch, M.C., San Martín, A., Ojeda, D., et al., Tacrolimus Causes a Blockage of Protein Secretion which Reinforces Its Immunosuppressive Activity and also Explains Some of Its Toxic Side-Effects, Transplant. Immunol., 2009, vol. 22, nos. 1–2, pp. 72–81.

    Article  CAS  Google Scholar 

  8. Penn, I., Cancers in Renal Transplant Recipients, Adv. Ren. Replace Ther., 2003, vol. 7, no. 2, pp. 147–156.

    Google Scholar 

  9. Anaya, F., Plaza, J., Sanz-Guajardo, D., et al., Cancer after Renal Transplantation, Transplant. Proc., 2003, vol. 35, no. 2, pp. 697–699.

    Article  PubMed  CAS  Google Scholar 

  10. Hui, R.L., Lide, W., Chan, J., et al., Association between Exposure to Topical Tacrolimus or Pimecrolimus and Cancers, Ann. Pharmacother., 2009, vol. 43, no. 12, pp. 1956–1963.

    Article  PubMed  CAS  Google Scholar 

  11. Bugelski, P.J., Volk, A., Walker, M.R., et al., Critical Review of Preclinical Approaches to Evaluate the Potential of Immunosuppressive Drugs to Influence Human Neoplasia, Int. J. Toxicol., 2010, vol. 29, no. 5, pp. 435–466.

    Article  PubMed  CAS  Google Scholar 

  12. Veness, M.J., Quinn, D.I., Ong, C.S., et al., Aggressive Cutaneous Malignancies Following Cardiothoracic Transplantation: The Australian Experience, Cancer, 1999, vol. 85, pp. 1758–1764.

    Article  PubMed  CAS  Google Scholar 

  13. Mistríkoví, J., Mrmusova’, M., Durmanova’, V., and Rajca’ni, J., Increased Neoplasm Development Due to Immunosuppressive Treatment with FK-506 in BALB/C Mice Persistently Infected with the Mouse Herpes Virus (MHV-72), Viral Immunol., 1999, vol. 12, no 3, pp. 237–247.

    Article  Google Scholar 

  14. Penn, I., Lymphomas Complicating Organ Transplantation, Transplant. Proc., 1983, vol. 15, no. 4, suppl. 1.

  15. Yarosh, D.B., Pena, A.V., et al., Calcineurin Inhibitors Decrease DNA Repair and Apoptosis in Human Keratinocytes Following Ultraviolet B Irradiation, J. Invest. Dermatol., 2005, vol. 125, no. 5, pp. 1020–1025.

    Article  PubMed  CAS  Google Scholar 

  16. Duncan, F.J., Wulff, B.C., Tober, K.L., et al., Clinically Relevant Immunosuppressants Influence UVB-Induced Tumor Size through Effects on Inflammation and Angiogenesis, Am. J. Transplant., 2007, vol. 7, no. 12, pp. 2693–2703.

    Article  PubMed  CAS  Google Scholar 

  17. Bonassi, S., Hagmar, L., Strömberg, U., et al., Chromosomal Aberrations in Lymphocytes Predict Human Cancer Independently of Exposure to Carcinogens: European Study Group on Cytogenetic Biomarkers and Health, Cancer Res., 2000, vol. 60, no. 6, pp. 1619–1625.

    PubMed  CAS  Google Scholar 

  18. Yu, Y., Yuzawa, K., Otsuka, M., and Fukao, K., Mutagenicity of the New Immunosuppressive Drugs, FK 506, and Spergualin, Transplant. Proc., 1993, vol. 25, no. 2, pp. 2116–2118.

    PubMed  CAS  Google Scholar 

  19. Özturk, Š., Ayna, T.K., Çefle, K., Palanduz, Ş., et al., Effect of Cyclosporin A and Tacrolimus on Sister Chromatid Exchange Frequency in Renal Transplant Patients, Genet. Test., 2008, vol. 12, no. 3, pp. 427–430.

    Article  PubMed  Google Scholar 

  20. Speit, G. and Haupter, S., On the Mechanism of Differential Giemsa Staining of Bromodeoxyuridine-Substituted Chromosomes, 2. Differences between the Demonstration of Sister Chromatid Differentiation and Replication Patterns, Hum. Genet., 1985, vol. 70, no. 2, pp. 126–129.

    Article  PubMed  CAS  Google Scholar 

  21. Shaffer, L.G., Slovak, M.L., and Campbell, L.J., An International System for Human Cytogenetic Nomenclature (ISCN), Basel: Karger, 2009.

    Google Scholar 

  22. Albertini, R.J., Anderson, D., Douglas, G.R., et al., IPCS Guidelines for the Monitoring of Genotoxic Effects of Carcinogens in Humans, Mutat. Res., 2000, vol. 463, pp. 111–117.

    Article  PubMed  CAS  Google Scholar 

  23. Fenech, M., Cytokinesis-Block Micronucleus Cytome Assay, Nat. Protoc., 2000, vol. 2, pp. 1084–1104.

    Article  Google Scholar 

  24. Surralle’s, J. and Natarajan, A.T., Human Lymphocytes Micronucleus Assay in Europe: An International Survey, Mutat. Res., 1997, vol. 392, nos. 1–2, pp. 165–174.

    Google Scholar 

  25. Armstrong, V.W. and Oellerich, M., New Developments in the Immunosuppressive Drug Monitoring of Cyclosporine, Tacrolimus, and Azathioprine, Clin. Biochem., 2001, vol. 34, no. 1, pp. 9–16.

    Article  PubMed  CAS  Google Scholar 

  26. Gutierrez-Dalmau, A. and Campistol, J.M., Immunosuppressive Therapy and Malignancy in Organ Transplant Recipients: A Systematic Review, Drugs, 2007, vol. 67, pp. 1167–1198.

    Article  PubMed  CAS  Google Scholar 

  27. Dworkin, A.M., Tober, K.L., Duncan, J., et al., Chromosomal Aberrations in UVB-Induced Tumors of Immunosuppressed Mice, Genes, Chromosomes Cancer., 2009, vol. 48, pp. 490–501.

    Article  PubMed  CAS  Google Scholar 

  28. Palanduz, S., Sever, M.S., Oztürk, S., et al., Genotoxic Potential of Cyclosporin A in Patients with Renal Transplantation, Cell Biol. Toxicol., 1999, vol. 15, no. 1, pp. 13–17.

    Article  PubMed  CAS  Google Scholar 

  29. Yuzawa, K., Fukao, K., Iwasaki, Y., and Hamaguchi, H., Mutagenicity of Cyclosporine against Human Cells, Transplant. Proc., 1987, vol. 19, no. 1, part 2, pp. 1218–1220.

    PubMed  CAS  Google Scholar 

  30. Japanese FK 506 Study Group: Japanese Study of FK 506 on Kidney Transplantation: The Benefit of Monitoring the Whole Blood FK 506 Concentration, Transplant. Proc., 1991, vol. 23, no. 6, pp. 3085–3088.

    Google Scholar 

  31. Oliveira, V.D., Zankl, H., and Rath, T., Mutagenic and Cytotoxic Effects of Immunosuppressive Drugs on Human Lymphocyte Cultures, Exp. Clin. Transplant., 2004, vol. 2, no. 2, pp. 273–279.

    PubMed  Google Scholar 

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Correspondence to S. Yuksel.

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Kurtoglu, E.L., Yuksel, S. Genotoxic effects of tacrolimus on human lymphocyte cells. Russ J Genet 48, 651–655 (2012). https://doi.org/10.1134/S1022795412050134

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  • DOI: https://doi.org/10.1134/S1022795412050134

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