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The investigation of mutagenic and carcinogenic effects by the ames test

Year 2013, Volume: 3 Issue: 2, 75 - 82, 30.01.2014

Abstract

Aim: Research has shown that the increased use of chemicals which are offered to consumers, sometimes without sufficient testing, has impacted human health and natural resources negatively. For this reason, many researchers have developed cost-effective test systems which can examine the carcinogenic and mutagenic activity of chemicals in a short time. Ames is an example of such a test system which can detect mutations at cellular level. Also the Ames test is accepted as a reliable method for specifically testing the toxic and mutagenic-carcinogenic effects of raw materials to be used in pharmaceuticals.

Material and Methods: In this study, the mutagenic and carcinogenic effect of methylphenidate, that is used for the treatment of Attention-Deficit Hyperactivity Disorder, was investigated by the Ames Salmonella/microsome test in the absence and presence of metabolic activation. The Ames Salmonella/microsome test can play an important role to identify the mutagenic effects of carcinogenic compounds and is used for the research and development of drugs. TA 98 and TA 100 strains were used in experiments. TA 98 is designed for frame-shift mutagens and TA 100 is designed for base-pair mutagens. The mutagenic activity was screened in two groups with or without S9 metabolic activation. The results were evaluated and the mean values were compared with positive and negative controls.

Results: According to the results of experiments conducted with TA98 and TA100, revertant colony count was not found higher than those spontaneous revertant colony count among all of the concentrations and as well as under the conditions of with and without S9 (p>0.05).

Conclusion: In conclusion, it was shown that methylphenidate was non-mutagenic for TA 98 and TA 100 with or without S9 metabolic activation.


Key words: Ames test, carcinogenicity, methylphenidate, S9 fraction, mutagenicity

References

  • Alzuet PR, Gaspes E, Ronco AE. Mutagenicity of Enviromental Samples from an Industrialized Area of the Rio de la Plata Estuary using the Salmonella/Microsomal Assay. Environ Toxicol Water Qual. 1996; 11: 231-2
  • Kim SJ, Rim KT, Kim HY, Yang JS. Mutagenicity of octane and tetrasodium pyrophosphate in bacterial reverse mutation (Ames) test. J Toxicol Sci. 2010; 35(4): 555-562.
  • Brusick D, Grotz VL, Slesinski R, Kruger CL, Hayes AW. The absence of genotoxicity of sucralose. Food Chem Toxicol. 2010; 48: 3067–3072.
  • Aygun N. Saç Boyası Uygulayıcılarında Mutajenik Aktivitelerin Saptanması. Ankara: Gazi Üniversitesi; 1996.
  • Karabay NÜ, Oguz MG. Cytogenetic and genotoxic effects of the insecticides, imidacloprid and methamidophos. Genet Mol Res. 2005; 4 (4): 653-662.
  • Fall M, Haddouk H, Morin JP, Forster R. Mutagenicity of benzyl chloride in the Salmonella/microsome mutagenesis assay depends on exposure conditions. Mutat Res. 2007; 633: 13-20.
  • Calvo TR, Cardoso CR, da Silva Moura AC, Dos Santos LC, Colus IM, Vilegas W, Varanda EA. Mutagenic Activity of Indigofera truxillensis and I. Suffruticosa. Aerial Parts. 2009; eCAM, 1-8.
  • Ziegelbauer HE, Aubrecht J, Kleinjans JC, Ahr HJ. Applications of toxicogenomics to study mechanisms of genotoxicity and carcinogenicity. Toxicol Lett. 2009; 186: 36-44.
  • Korkmaz B. Bazı 2-sübstitüe Perimidin Bileşiklerinin Mutajenik aktivitelerinin Ames Mutajenite Testi ile Belirlenmesi. Eskişehir: Anadolu Üniversitesi; 2005.
  • Murray RK, Mayes PA, Granner DDK, Rodwell VW. ed: Gülriz Menteş Harper’in Biyokimyası. İstanbul: Barış Kitabevi; 1993. s:811-917.
  • Temizkan GO. Moleküler Genetik. İstanbul: İstanbul Üniversitesi Yayınları; 1996. s:281.
  • Barile FA. Principle of Toxicology testing. Chapter 15: New York; 2008. p:209-228.
  • Mortelmans K, Zeiger E. The Ames Salmonella/ microsome mutagenicity assay. Mutat Res. 2000; 455: 29-60.
  • Dunnick JK, Hailey JR. Experimental studies on the long-term effects of methylphenidate hydrochloride. Toxicol. 1995; 103: 77-84.
  • Challman TD, Lipsky JJ. Methylphenidate: its pharmacology and uses. Mayo Clin Proc. 2000; 75(7): 711-721.
  • Sood A, Barton DL, Loprinzi CL. Use of methylphenidate in patients with cancer. Am J Hosp & Palliat Med. 2006; 23(1): 35-40.
  • Kimko HC, Cross JT, Abernethy DR. Pharmacokinetics and clinical effectiveness of methylphenidate. Clin Pharmacokinet. 1999; 37(6): 457-70.
  • National Toxicology Program. Toxicology and Carcinogenesis Studies of Methylphenidate Hydrochloride (CAS No. 298-59-9) in F344/N Rats and B6C3F1 Mice (Feed Studies). Natl Toxicol Program Tech Rep Ser. 1995; 439: 1-299.
  • Kier LD. Use of the Ames test in toxicology. Regul Toxicol Pharmacol. 1985; 5(1): 59-64.
  • Ames BN, Durston WE, Yamasaki E, Lee FD. Carcinogens are Mutagens: A Simple Test System Combining Liver Homogenates for Activation and Bacteria for Detection. Proc Nat Acad Sci. 1973; 70(8): 2281-2285.
  • El-Zein AR, Abdel-Rahman SZ, Hay MJ, Lopez MS, Bondy ML, Morris DL, Legator MS. Cytogenetic effects in children treated with methylphenidate. Cancer Lett. 2005; 230: 284-291.
  • Ashton H, Gallagher P, Moore B. The adult psychiatrist’s dilemma: psychostimulant use in attention deficit/hyperactivity disorder. J Psychopharmacol. 2006; 20(5): 602-610.
  • Teo ST, San RH, Wagner VO, Gudi R, Stirling DI, Thomas SD, Khetani VD. d-Methylphenidate is non-genotoxic in in vitro and in vivo assays. Mutat Res. 2003; 537: 67-69.
  • Dunnick JK, Elwell MR, Haseman JK. Decreased incidence of spontaneous mammary gland neoplasms in female F344 rats treated with amphetamine, methylphenidate, or codein. Cancer Lett. 1996; 102: 77-83.
  • Gallaway SM, Armstrong MJ, Reuben C, Colman S, Brown B, Cannon C, Bloom AD, Nakamura F, Ahmed M, Duk S. Chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells: evaluations of 108 chemicals. Environ Mol Mutagen. 1987; 10: 1-175.
  • Walker AP, Dumars KW. Commonly used pediatric drugs, sister chromatid exchanges and the cell cycle. Am J Hum Genet. 1977; 29: 110A.
  • Matthews EJ, Spalding RW, Tennant RW. Transformation of BALB/c3T3 cells: V. Transformation responses of 168 chemicals compared with mutagenicity in Salmonella and carcinogenicity in rodent bioassay. Environ Health Perspect. 1993; 101: 347-482.
  • Rudd CJ, Mitchell AD, Spalding J. Mouse lymphoma cell mutagenesis assay of coded chemicals incorporating analyses of the colony size distributions. Environ Mol Mutagen. 1983; 5: 419.
  • Andreazza AC, Frey BN, Valvassori SS, Zanotto C, Gomes KM, Comim CM, Cassini C, Stertz L, Ribeiro LC, Quevedo J, Kapczinski F, Berk M, Gonçalves CA. DNA damage in rats after treatment with methylphenidate. Prog Neuropsychopharmocol Biol Psychiatry. 2007; 31(6): 1282-1288.
  • Witt KL, Malarkey DE, Hobbs CA, Davis JP, Kissling GE, Caspary W, Travlos G, Recio L. No Increases in Biomarkers of Genetic Damage or Pathological Changes in Heart and Brain Tissues in Male Rats Administered Methylphenidate Hydrochloride (Ritalin) for 28 Days. Environ Mol Mutagen. 2010; 51(1): 80-88.
  • International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals; 1995.
  • International Conference on Harmonisation of Technical Requirements for registration of Pharmaceuticals for Human Use. Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals s2B; 1997.
  • Bonassi S, Znaor A, Norppa H, Hagmar L. Chromosomal aberrations and risk of cancer in humans: an epidemiologic perspective. Cytogenet Genome Res. 2004; 104(1-4): 376-382.
  • Bonassi S, Norppa H, Ceppi M, Strömberg U, Vermeulen R, Znaor A, Wasilewska AC, Fabianova E, Fucic A, Gundy S, Hansteen IL, Knudsen LE, Lazutka, Rossner P, Sram RJ, Boffetta P. Chromosomal aberration frequency in lymphocytes predicts the risk of cancer: results from a pooled cohort study of 22 358 subjects in 11 countries. Carcinogen. 2008; 29(6 ): 1178-1183.
  • Witt K, Shelby MD, Itchon-Ramos N, Faircloth M, Kissling GE, Chrisman AK, Ravi H, Murli H, Mattison DR, Kollins SH. Methylphenidate and Amphetamine Do Not Induce Cytogenetic Damage in Lymphocytes of Children With ADHD. J Am Acad Child Adolesc Psychiatry. 2008; 47(12): 1375-1383.
  • International Conference on Harmonisation of Technical Requirements for registration of Pharmaceuticals for Human Use. Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals S2B; 1997.
  • Ponsa I, Ramos-Quiroga JA, Ribasés M, Bosch R, Bielsa A, Ordeig MT, Morell M, Miro R, Cid R, Estivill, Casas M, Bayés M, Cormand B, Hervas A. Absence of cytogenetic effects in children and adults with attentiondeficit /hyperactivity disorder treated with methylphenidate. Mutat Res. 2009; 666: 44-49.
  • Walitza S, Werner B, Romanos M, Warnke A, Gerlach M, Stopper H. Does methylphenidate cause a cytogenetic effect in children with attention deficit hyperactivity disorder? Environ Health Perspect. 2007; 115(6): 936-940.
  • Suter W, Martus HJ, Elhajouji A. Methylphenidate is not clastogenic in cultured human lymphocytes and in the mouse bone-marrow micronucleus test. Mutat Res. 2006; 607: 153-159.
  • Tucker JD, Suter W, Petibone DM, Thomas RA, Bailey NL, Zhou Y, Zhao Y, Muniz R, Kumar V. Cytogenetic assessment of methylphenidate treatment in pediatric patients treated for attention deficit hyperactivity disorser. Mutat Res. 2009; 677: 53-58.

Mutajenik-karsinojenik etkinin ames testi ile araştırılması

Year 2013, Volume: 3 Issue: 2, 75 - 82, 30.01.2014

Abstract

Amaç: Kimyasalların insan hayatında daha fazla yer alması ve buna bağlı olarak kimyasal maddelerin gerekli güvenlik testlerinden geçmeden kullanılmaya başlanmasıyla birlikte kimyasalların insan sağlığı ve doğal kaynaklar üzerine olumsuz etkileri ortaya çıkmıştır. Bu sebeple birçok araştırmacı, kimyasalların karsinojenik ve mutajenik aktivitelerini inceleyip kısa zamanda sonuç veren düşük maliyetli mutajenite test sistemleri geliştirmişlerdir. Kimyasallar tarafından meydana gelen mutasyonların hücre düzeyinde belirlenmesi amacıyla kullanılan kısa zamanlı test sistemlerinden biri de Ames testidir. Ames testi, özellikle ilaç ham maddesi olarak kullanılmak istenen test maddelerinin toksik, mutajenik-karsinojenik etkilerini incelemek için güvenilir yöntemler arasında kabul edilmektedir.

Gereç ve Yöntem: Bu çalışma ile ilaçların geliştirilmesinde ve karsinojen maddelerin mutajenitelerinin saptanmasında kullanılan önemli bir mutajenite testi olarak kabul edilen Ames Salmonella/mikrozom Testi uygulanarak dikkat eksikliği ve hiperaktivite bozukluğunda kullanılan ilaç ham maddesi metilfenidatın mutajenik ve karsinojenik etkisi araştırılmıştır. Yöntemde Salmonella typhimurium TA 100 ve TA 98 suşları ile çalışılmıştır.

Bulgular: TA 100 baz çifti değişimine, TA 98 ise çerçeve kaymasına yol açan mutajenlerin belirlenmesi için kullanılmıştır. Deneyler S9’lu ve S9’suz olmak üzere iki grup halinde gerçekleştirilmiştir. Test sonuçlarının ortalaması alınarak, pozitif ve negatif kontrol grupları ile karşılaştırılmış ve değerlendirilmiştir.

Sonuç: Çalışmamızda, metilfenidatın TA 100 ve TA 98 suşları ile S9 varlığında ve yokluğunda mutajenik aktiviteye sahip olmadığı gösterilmiştir.


Anahtar Kelimeler : Ames testi, karsinojenite, metilfenidat, mutajenite, S9 fraksiyonu

References

  • Alzuet PR, Gaspes E, Ronco AE. Mutagenicity of Enviromental Samples from an Industrialized Area of the Rio de la Plata Estuary using the Salmonella/Microsomal Assay. Environ Toxicol Water Qual. 1996; 11: 231-2
  • Kim SJ, Rim KT, Kim HY, Yang JS. Mutagenicity of octane and tetrasodium pyrophosphate in bacterial reverse mutation (Ames) test. J Toxicol Sci. 2010; 35(4): 555-562.
  • Brusick D, Grotz VL, Slesinski R, Kruger CL, Hayes AW. The absence of genotoxicity of sucralose. Food Chem Toxicol. 2010; 48: 3067–3072.
  • Aygun N. Saç Boyası Uygulayıcılarında Mutajenik Aktivitelerin Saptanması. Ankara: Gazi Üniversitesi; 1996.
  • Karabay NÜ, Oguz MG. Cytogenetic and genotoxic effects of the insecticides, imidacloprid and methamidophos. Genet Mol Res. 2005; 4 (4): 653-662.
  • Fall M, Haddouk H, Morin JP, Forster R. Mutagenicity of benzyl chloride in the Salmonella/microsome mutagenesis assay depends on exposure conditions. Mutat Res. 2007; 633: 13-20.
  • Calvo TR, Cardoso CR, da Silva Moura AC, Dos Santos LC, Colus IM, Vilegas W, Varanda EA. Mutagenic Activity of Indigofera truxillensis and I. Suffruticosa. Aerial Parts. 2009; eCAM, 1-8.
  • Ziegelbauer HE, Aubrecht J, Kleinjans JC, Ahr HJ. Applications of toxicogenomics to study mechanisms of genotoxicity and carcinogenicity. Toxicol Lett. 2009; 186: 36-44.
  • Korkmaz B. Bazı 2-sübstitüe Perimidin Bileşiklerinin Mutajenik aktivitelerinin Ames Mutajenite Testi ile Belirlenmesi. Eskişehir: Anadolu Üniversitesi; 2005.
  • Murray RK, Mayes PA, Granner DDK, Rodwell VW. ed: Gülriz Menteş Harper’in Biyokimyası. İstanbul: Barış Kitabevi; 1993. s:811-917.
  • Temizkan GO. Moleküler Genetik. İstanbul: İstanbul Üniversitesi Yayınları; 1996. s:281.
  • Barile FA. Principle of Toxicology testing. Chapter 15: New York; 2008. p:209-228.
  • Mortelmans K, Zeiger E. The Ames Salmonella/ microsome mutagenicity assay. Mutat Res. 2000; 455: 29-60.
  • Dunnick JK, Hailey JR. Experimental studies on the long-term effects of methylphenidate hydrochloride. Toxicol. 1995; 103: 77-84.
  • Challman TD, Lipsky JJ. Methylphenidate: its pharmacology and uses. Mayo Clin Proc. 2000; 75(7): 711-721.
  • Sood A, Barton DL, Loprinzi CL. Use of methylphenidate in patients with cancer. Am J Hosp & Palliat Med. 2006; 23(1): 35-40.
  • Kimko HC, Cross JT, Abernethy DR. Pharmacokinetics and clinical effectiveness of methylphenidate. Clin Pharmacokinet. 1999; 37(6): 457-70.
  • National Toxicology Program. Toxicology and Carcinogenesis Studies of Methylphenidate Hydrochloride (CAS No. 298-59-9) in F344/N Rats and B6C3F1 Mice (Feed Studies). Natl Toxicol Program Tech Rep Ser. 1995; 439: 1-299.
  • Kier LD. Use of the Ames test in toxicology. Regul Toxicol Pharmacol. 1985; 5(1): 59-64.
  • Ames BN, Durston WE, Yamasaki E, Lee FD. Carcinogens are Mutagens: A Simple Test System Combining Liver Homogenates for Activation and Bacteria for Detection. Proc Nat Acad Sci. 1973; 70(8): 2281-2285.
  • El-Zein AR, Abdel-Rahman SZ, Hay MJ, Lopez MS, Bondy ML, Morris DL, Legator MS. Cytogenetic effects in children treated with methylphenidate. Cancer Lett. 2005; 230: 284-291.
  • Ashton H, Gallagher P, Moore B. The adult psychiatrist’s dilemma: psychostimulant use in attention deficit/hyperactivity disorder. J Psychopharmacol. 2006; 20(5): 602-610.
  • Teo ST, San RH, Wagner VO, Gudi R, Stirling DI, Thomas SD, Khetani VD. d-Methylphenidate is non-genotoxic in in vitro and in vivo assays. Mutat Res. 2003; 537: 67-69.
  • Dunnick JK, Elwell MR, Haseman JK. Decreased incidence of spontaneous mammary gland neoplasms in female F344 rats treated with amphetamine, methylphenidate, or codein. Cancer Lett. 1996; 102: 77-83.
  • Gallaway SM, Armstrong MJ, Reuben C, Colman S, Brown B, Cannon C, Bloom AD, Nakamura F, Ahmed M, Duk S. Chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells: evaluations of 108 chemicals. Environ Mol Mutagen. 1987; 10: 1-175.
  • Walker AP, Dumars KW. Commonly used pediatric drugs, sister chromatid exchanges and the cell cycle. Am J Hum Genet. 1977; 29: 110A.
  • Matthews EJ, Spalding RW, Tennant RW. Transformation of BALB/c3T3 cells: V. Transformation responses of 168 chemicals compared with mutagenicity in Salmonella and carcinogenicity in rodent bioassay. Environ Health Perspect. 1993; 101: 347-482.
  • Rudd CJ, Mitchell AD, Spalding J. Mouse lymphoma cell mutagenesis assay of coded chemicals incorporating analyses of the colony size distributions. Environ Mol Mutagen. 1983; 5: 419.
  • Andreazza AC, Frey BN, Valvassori SS, Zanotto C, Gomes KM, Comim CM, Cassini C, Stertz L, Ribeiro LC, Quevedo J, Kapczinski F, Berk M, Gonçalves CA. DNA damage in rats after treatment with methylphenidate. Prog Neuropsychopharmocol Biol Psychiatry. 2007; 31(6): 1282-1288.
  • Witt KL, Malarkey DE, Hobbs CA, Davis JP, Kissling GE, Caspary W, Travlos G, Recio L. No Increases in Biomarkers of Genetic Damage or Pathological Changes in Heart and Brain Tissues in Male Rats Administered Methylphenidate Hydrochloride (Ritalin) for 28 Days. Environ Mol Mutagen. 2010; 51(1): 80-88.
  • International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals; 1995.
  • International Conference on Harmonisation of Technical Requirements for registration of Pharmaceuticals for Human Use. Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals s2B; 1997.
  • Bonassi S, Znaor A, Norppa H, Hagmar L. Chromosomal aberrations and risk of cancer in humans: an epidemiologic perspective. Cytogenet Genome Res. 2004; 104(1-4): 376-382.
  • Bonassi S, Norppa H, Ceppi M, Strömberg U, Vermeulen R, Znaor A, Wasilewska AC, Fabianova E, Fucic A, Gundy S, Hansteen IL, Knudsen LE, Lazutka, Rossner P, Sram RJ, Boffetta P. Chromosomal aberration frequency in lymphocytes predicts the risk of cancer: results from a pooled cohort study of 22 358 subjects in 11 countries. Carcinogen. 2008; 29(6 ): 1178-1183.
  • Witt K, Shelby MD, Itchon-Ramos N, Faircloth M, Kissling GE, Chrisman AK, Ravi H, Murli H, Mattison DR, Kollins SH. Methylphenidate and Amphetamine Do Not Induce Cytogenetic Damage in Lymphocytes of Children With ADHD. J Am Acad Child Adolesc Psychiatry. 2008; 47(12): 1375-1383.
  • International Conference on Harmonisation of Technical Requirements for registration of Pharmaceuticals for Human Use. Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals S2B; 1997.
  • Ponsa I, Ramos-Quiroga JA, Ribasés M, Bosch R, Bielsa A, Ordeig MT, Morell M, Miro R, Cid R, Estivill, Casas M, Bayés M, Cormand B, Hervas A. Absence of cytogenetic effects in children and adults with attentiondeficit /hyperactivity disorder treated with methylphenidate. Mutat Res. 2009; 666: 44-49.
  • Walitza S, Werner B, Romanos M, Warnke A, Gerlach M, Stopper H. Does methylphenidate cause a cytogenetic effect in children with attention deficit hyperactivity disorder? Environ Health Perspect. 2007; 115(6): 936-940.
  • Suter W, Martus HJ, Elhajouji A. Methylphenidate is not clastogenic in cultured human lymphocytes and in the mouse bone-marrow micronucleus test. Mutat Res. 2006; 607: 153-159.
  • Tucker JD, Suter W, Petibone DM, Thomas RA, Bailey NL, Zhou Y, Zhao Y, Muniz R, Kumar V. Cytogenetic assessment of methylphenidate treatment in pediatric patients treated for attention deficit hyperactivity disorser. Mutat Res. 2009; 677: 53-58.
There are 40 citations in total.

Details

Primary Language Turkish
Journal Section Articles
Authors

Selin Oğuz This is me

Gülden Z. Omurtag

Feyza Arıcıoğlu This is me

Semra Şardaş This is me

Publication Date January 30, 2014
Submission Date January 30, 2014
Published in Issue Year 2013 Volume: 3 Issue: 2

Cite

APA Oğuz, S., Omurtag, G. Z., Arıcıoğlu, F., Şardaş, S. (2014). Mutajenik-karsinojenik etkinin ames testi ile araştırılması. Clinical and Experimental Health Sciences, 3(2), 75-82. https://doi.org/10.5455/musbed.20130620095205
AMA Oğuz S, Omurtag GZ, Arıcıoğlu F, Şardaş S. Mutajenik-karsinojenik etkinin ames testi ile araştırılması. Clinical and Experimental Health Sciences. February 2014;3(2):75-82. doi:10.5455/musbed.20130620095205
Chicago Oğuz, Selin, Gülden Z. Omurtag, Feyza Arıcıoğlu, and Semra Şardaş. “Mutajenik-Karsinojenik Etkinin Ames Testi Ile araştırılması”. Clinical and Experimental Health Sciences 3, no. 2 (February 2014): 75-82. https://doi.org/10.5455/musbed.20130620095205.
EndNote Oğuz S, Omurtag GZ, Arıcıoğlu F, Şardaş S (February 1, 2014) Mutajenik-karsinojenik etkinin ames testi ile araştırılması. Clinical and Experimental Health Sciences 3 2 75–82.
IEEE S. Oğuz, G. Z. Omurtag, F. Arıcıoğlu, and S. Şardaş, “Mutajenik-karsinojenik etkinin ames testi ile araştırılması”, Clinical and Experimental Health Sciences, vol. 3, no. 2, pp. 75–82, 2014, doi: 10.5455/musbed.20130620095205.
ISNAD Oğuz, Selin et al. “Mutajenik-Karsinojenik Etkinin Ames Testi Ile araştırılması”. Clinical and Experimental Health Sciences 3/2 (February 2014), 75-82. https://doi.org/10.5455/musbed.20130620095205.
JAMA Oğuz S, Omurtag GZ, Arıcıoğlu F, Şardaş S. Mutajenik-karsinojenik etkinin ames testi ile araştırılması. Clinical and Experimental Health Sciences. 2014;3:75–82.
MLA Oğuz, Selin et al. “Mutajenik-Karsinojenik Etkinin Ames Testi Ile araştırılması”. Clinical and Experimental Health Sciences, vol. 3, no. 2, 2014, pp. 75-82, doi:10.5455/musbed.20130620095205.
Vancouver Oğuz S, Omurtag GZ, Arıcıoğlu F, Şardaş S. Mutajenik-karsinojenik etkinin ames testi ile araştırılması. Clinical and Experimental Health Sciences. 2014;3(2):75-82.

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