Evaluation of genotoxic activity of tenofovir disoproxil fumarate in human peripheral lymphocytes

Year 2016, Volume: 41 Issue: 2, 229 - 235, 30.06.2016

Kübra Kurt Lale Dönbak , Ahmet Kayraldız

Abstract

Purpose: Antiretroviral drugs used in the treatment of HIV (Human Immünodeficiency Virus) iınfection, treat by preventing the proliferation of HIV in human body. People with HIV have to use this drugs for lifelong because of inability of the drugs to eradicate the viruses. In this study, we investigated the in vitro genotoxic activity of tenofovir disoproxil fumarate one of the antiretroviral drugs, in human peripheral lymphocytes. 
Material and Methods: The cells were treated with four different concentrations of tenofovir disoproxil fumarate for 24 and 48 hours. The levels of sister chromatid exchanges, chromosomal aberrations, and micronucleus in the cells were examined for the genotoxic activity of tenofovir disoproxil fumarate. Mitotic index, proliferation index, and nucleer division index of treated cells were also determined for the cytotoxic effect of tenofovir disoproxil fumarate. 
Results: There was no significant differences in the level of sister chromatid exchanges, chromosomal aberrations, and micronucleus in human lyphocytes treated with all concetrations of tenofovir disoproxil fumarate for all treatment period as compared to control group. Similarly, it was observed that treatment of tenofovir disoproxil fumarate did not affect the mitotic index, proliferation index, and nucleer division index values. 
Conclusion: As a result, in this study, it is demonstrated that tenofovir disoproxil fumarate did not have genotoxic or cytotoxic effect in the human peripheral lymphocytes.

Keywords

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Tenofovir disoproksil fumaratın insan lenfositlerinde genotoksik aktivitesinin incelenmesi

Abstract

Amaç: HIV (Human Immünodeficiency Virus) enfeksiyonunun tedavisinde kullanılan antiretroviral ilaçlar, HIV virüsünün vücutta çoğalmasını ve etkinleşmesini engelleyerek tedavi sağlarlar. Bu ilaçlar virüsü eradike etmediğinden, hastaların viral replikasyonu baskılamak amacıyla ilaçları ömür boyu kullanmaları gerekmektedir. Bu çalışmada antiretroviral ilaçlardan birisi olan tenofovir disoproksil fumaratın insan periferal lenfositlerindeki in vitro genotoksik aktivitesi araştırılmıştır. Gereç ve Yöntem: Bu maçla hücreler, tenofovir disoproksil fumaratın dört farklı konsantrasyonuyla (2,5, 5, 10, 20 µg/ml) 24 ve 48 saat süreyle muamele edilmiştir. Tenofovir disoproksil fumaratın olası genotoksik aktivitesi için hücrelerdeki kardeş kromatid değişimi, kromozom anormalliği ve mikronükleus düzeyleri incelenmiştir. Sitotoksik etkiyi saptamak amacıyla muamele edilmiş hücrelerde ayrıca mitotik indeks, proliferasyon indeksi ve nükleer bölünme indeksi belirlenmiştir. Bulgular: Tenofovir disoproksil fumarat etken maddesinden hazırlanan dört farklı doz ile 24 ve 48 saat muamele edilen hücrelerde kardeş kromatid değişimi, kromozomal anormallik ve mikronükleus değerlerinde kontrol grubuna kıyasla önemli bir farklılık saptanmamıştır. Aynı şekilde tenofovir disoproksil fumarat etken maddesi ile muamelenin mitotik indeks, proliferasyon indeksi ve nükleer bölünme indeksi değerlerini etkilemediği gözlenmiştir. Sonuç: Bu çalışmada tenofovir disoproksil fumaratın insan periferal lenfositlerinde genotoksik ve sitotoksik etki göstermediği saptanmıştır.

Keywords

Genotoksik risk, tenofovir disoproksil fumarat, kromozomal anormallikler

References

• Serter D. Türkiye'de ve dünyada cinsel yolla bulaşan enfeksiyonlar ve HIV/AIDS. Türkiye Klinikleri Tıp Bilimleri Dergisi. 2006;2:1-5.
• Açıoğlu S, Ünal S. Cinsel Yolla Bulaşan Hastalıkların Epidemiyolojisi. Ankara, Bilim Tıp Yayınevi, 2001.
• Tümer A. AİDS nedir? Dünyada ve Türkiye’de HIV/AIDS. AIDS_web2014.pdf (Erişim tarihi Haziran 2015).
• Sulukan EE, Küçükoğlu K, Gül Hİ. AIDS ve tedavisinde kullanılan ilaçlar. Ankara Eczacılık Fakültesi Dergisi. 2009;38:47-78.
• Türker N, Örmen B. Antiretroviral tedavi. İnfeksiyon Dergisi. 2006;20:207-17.
• Hammer SM, Eron JJ, Reiss P, Schooley RT, Thompson MA, Walmsley S et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society- USA Panel. JAMA. 2008;300:555-70.
• Karaosmanoğlu HK, Aydın ÖA, Özyiğit F, İnce ER, Korkusuz R, Nazlıcan Ö. Antiretroviral tedavi ile ilişkili yan etkiler: 260 HIV/AIDS olgusunun değerlendirilmesi. 2013;6:118-21. Tıp Dergisi.
• Calmy A, Hirschel B, Cooper DA, Carr A. A new era of antiretroviral drug toxicity. Antivir Ther. 2009;14:165-79.
• Brambilla G, Mattioli F, Robbiano L, Martelli A. Studies on genotoxicity and carcinogenicity of antibacterial, antiviral, antimalarial and antifungal drugs. Mutagenesis. 2012;27:387-413.
• Wutzler P, Thust R. Genetic risks of antiviral nucleoside analogues-a survey. Antiviral Res. 2001;49:55-74.
• Gallant JE, Deresinski S. Tenofovir disoproxil fumarate. Clin Infect Dis. 2003;37:944-50.
• Perry P, Thompson EJ. The methodology of sister chromatid Mutagenicity Test Procedures. (Eds BJ Kilbey, M Legator, W Nichols, C Ramel):495-529. New York, Elsevier, 1984. In: Handbook of
• Evans HJ. Human peripheral blood lymphocytes for the analysis of chromosome aberrations in mutagen tests. In: Hahdbook of Mutagenicity Test Producers. 2nd ed, (Eds BJ Kilbey, M Legator, W Nichols, C Ramel):405-27. New York, Elsevier, 1984.
• Rothfuss A, Schutz P, Bochum S, Volm T, Eberhardt E, Kreienberg R, et al. Induced micronucleus frequencies in peripheral lymphocytes as a screening test for carries of a BRCA1 mutation in breast cancer families. Cancer Research. 2000;60:390-4.
• Müller L, Kikuchi Y, Probst G, Schechtman L, Shimada H, Sofuni T, et al. ICH-harmonised guidances on genotoxicity testing of pharmaceuticals: evolution, reasoning and impact. Mutat. Res. 1999;436:195-225.
• US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry. S1B. Testing for Carcinogenicity of Pharmaceuticals. 1997.
• Brambilla G, Martelli A. Genotoxic and carcinogenic risk to humans of drug nitrite interaction products. Mutat Res. 2007;635:17-52.
• Snyder RD, Green JW. A review of the genotoxicity of marketed pharmaceuticals. Mutat Res. 2001;488:151-69.
• Snyder RD. An update on the genotoxicity and carcinogenicity of marketed pharmaceuticals with reference to in silico predictivity. Environ Mol Mutagen. 2009;50:435-50.
• Ayers KM, Clive D, Tucker WE Jr, Hajian G, Miranda P. Nonclinical toxicology studies with zidovudine: genetic toxicity tests and carcinogenicity bioassays in mice and rats. Fundam Appl Toxicol. 1996;32:148-58.
• Zeller A, Koenig J, Schmitt G, Singer T, Guerard M. Genoticity profile of azidothymidine in vitro. Toxicol Sci. 2013;135:317-27.
• Sussman A, Olivero OA, Meng Q, Pietras SM, Poirier MC, O’Neill JP et al. genotoxicity of 3'-azido- 3'-deoxythymidine in the human lymphoblastoid cell line, incorporation, mutant frequency and spectrum of deletion mutations in HPRT. Mutat Res. 1999;429:249-59. between DNA
• Kaushik A, Saini R, Rana AC, Kaushik P. Geno- cytotoxicity study of antiretroviral drug used in HIV- therapy. Journal of Innovative Biology. 2014;2:63-7.
• Bayram S, Topaktaş M. Confirmation of the chromosome damaging effects of lamivudine in vitro human peripheral blood lymphocytes. Environ Mol Mutagen. 2008;49:328-33.
• Carter MM,Torres SM, Cook DL Jr, McCash CL, Yu M, Walker VE et al. Relative mutagenic potencies of several nucleoside analogs, alone or in drug pairs, at the HPRT and TK loci of human TK6 lymphoblastoid cells. Environ Mol Mutagen. 2007;48:239-47.