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Antigenotoxicity, SMART, Streptozotocin, Cyclophosphamide, White tea, Cancer drug
In the present study, it was aimed to determine the antigenotoxic activity of white tea against the genotoxic effect caused by two different alkylating antineoplastic cancer drugs streptozotocin (STZ) and cyclophosphamide (CP) in Drosophila melanogaster through the somatic mutation and recombination test (SMART). During the application of SMART, two different mutant strains were used in the genome of D. melanogaster, with the determinant genes being recessive flare (flr3) and multiple wing hairs (mwh), respectively. Trans-heterozygous larvae of 72±hours, obtained through the crossbreeding of these two mutant strains, were chronically fed with white tea extract of different concentrations (0.625, 1.25, 2.50, and 5 mg/mL). In our study, the LD50 values of the relevant drugs were also found (STZ: 0.25 mg/mL, CP: 2.5 mg/mL), and it was determined that both drugs have a fairly high genotoxic effect (p<0.05). Afterward, white tea extracts of different concentrations were applied to larvae simultaneously with cancer drugs. From the data obtained, it was determined that white tea extract significantly reduced the clone induction frequency (CIF) in all treatment groups, by suppressing mutations enabling the formation of spots in wings, in parallel with the increasing concentration. Furthermore, when the inhibition percentage rates were subjected to examination in order to determine white tea’s reduction rate of the genotoxic effect caused by cancer drugs, it was determined that the relevant rate was 55.79% in the 0.25 STZ+2.5 White Tea treatment group, and 60.00% in the 2.5 CP+5 White Tea treatment group. In conclusion, it was concluded that streptozotocin and cyclophosphamide drugs used in cancer treatments might create genotoxic effects even in healthy cells, and these effects might be reduced by additional white tea consumption
2. de Godoy RCB, Deliza R, Gheno, LB, Licodiedoff S, Frizon CNT, Ribani RH, dos Santos GG. Consumer perceptions, attitudes and acceptance of new and traditional mate tea products. Food Res Int 2013;53(2), 801-807.
3. Dias TR, Carrageta DF, Ales MG, Oliveira PF, Silva BM. White Tea. In Nonvitamin and Nonmineral Nutritional Supplements 2019;437-45
4. Tijburg LB, Mattern T, Folts JD, Weisgerber UM, Katan MB. Tea flavonoids and cardiovascular disease: a review. Crit Rev Food Sci Nutr 1997; 37:771–85.
5. Pinto MS. Tea: a new perspective on health benefits. Food Res Int 2013; 53, 558-567.
6. Santana-Rios, G, Orner GA, Amantana A, Provost C, Wu SY, Dashwood RH. Potent antimutagenic activity of white tea in comparison with green tea in the Salmonella assay. Mutat Res 2001; 495:61–74.
7. Yogeshwer OS. Tea and Cancer Chemoprevention: A Comprehensive Review. Asian Pacific Journal of Cancer Prevention 2007; 8,155-166.
8. Pérez-Burillo S, Giménez R, Rufián-Henares JA, Pastoriza S. Effect of brewing time and temperature on antioxidant capacity and phenols of white tea: Relationship with sensory properties. Food chemistry 2018; 248, 111-118.
9. Kaur A, Farooq S, Sehgal AA. comparative study of antioxidant potential and phenolic content in white (Silver needle), green and black tea. Current Nutrition & Food Science 2019; 15(4), 415-420.
10.Almajano MP, Vila I, Ginés S. Neuroprotective effects of white tea against oxidative stress-induced toxicity in striatal cells. Neurotoxicity research 2011;20(4), 372-378.
11. Kumar M, Sharma VL, Sehgal A, Jain M. Protective effects of green and white tea against benzo (a) pyrene induced oxidative stress and DNA damage in murine model”, Nutrition and cancer 2012;64(2), 300-306.
12. Pérez-Jiménez A, Peres H, Rubio VC, Oliva-Teles A, The effect of dietary methionine and white tea on oxidative status of gilthead sea bream (Sparus aurata). Br J Nutr 2012; 108(7), 1202-1209.
13. Al-Shiekh A, Al-Shati, A, Sarhan M. Effect of White Tea Extract on Antioxidant Enzyme Activities of Streptozotocin–Induced Diabetic Rats 2014; 6(2) 17-30
14. Hajiaghaalipour F, Kanthimathi MS, Sanusi J, Rajarajeswaran J. White tea (Camellia sinensis) inhibits proliferation of the colon cancer cell line, HT-29, activates caspases and protects DNA of normal cells against oxidative damage. Food chemistry 2015; 169, 401-410.
15. Yang CS, Wang ZY. Tea and cancer. J Natl Cancer Inst 1993; 85:1038-1049.
16. Gramza A, Korczak J. Tea constituents (Camellia sinensis L.) as antioxidants in lipid systems. Trends Food Sci Tech 2005; 16(8): 351-358.
17. Zhao L, La VD. Grenier, D. Antibacterial, antiadherence, antiprotease, and anti-inflammatory activities of various tea extracts: Potential benefits for periodontal diseases. J. Med. Food 2013;16, 428–436.
18. Roghani M, Baluchnejadmojarad T. Hypoglycemic and hypolipidemic effect and antioxidant activity of chronic epigallocatechin-gallate in streptozotocin-diabetic rats. Pathophysiology 2010; 17(1): 55-9.
19. Komes D, Horzic D, Belscak A, Kovacevic Ganic K, Bljak A. Determination of caffeine content in tea and maté tea by using different methods. Czech J. Food Sci 27, 213- 216.
20. Li X, Smid SD, Lin J. et al. Neuroprotective and Anti-Amyloid β Effect and Main Chemical Profiles of White Tea: Comparison Against Green, Oolong and Black Tea. Molecules 2019; 24(10), 1926.
21. Tomaszewska E, Muszyński S, Dobrowolski P. et al. White tea is more effective in preservation of bone loss in adult rats co-exposed to lead and cadmium compared to black, red or green tea. Annals of Animal Science 2018; 18(4), 937-953.
22. Wadler S, Schwartz EL. Antineoplastic activity of the combination of interferon and cytotoxic agents against experimental and human malignancies: a review. Cancer Research 1990; 50(12), 3473-3486.
23. Corrie PG. Cytotoxic chemotherapy: clinical aspects. Medicine 2008;36(1):24-28.
24. Turker A, Kayaalp O. Kanser kemoterapisinin esasları ve antineoplastik ilaçlar [Principles of cancer chemotherapy and antineoplastic drugs]. İçinde Kayaalp O (ed): Rasyonel Tedavi Yönünden Tıbbi Farmakoloji [Medical Pharmacology in Terms of Rational Therapy]. Pelikan Yayıncılık, Ankara 2009;331
25. Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 2001; 50:537-46.
26. Lekskulchai V. Quantitation of anticancer drugs-Cyclophosphamide and ifosfamide in urine and water sewage samples by gas chromatography-mass spectrometry. International Journal of Occupational Medicine and Environmental Health 2016;29(5), 815.
27. Jennings BH. Drosophila-a versatile model in biology & medicine. Mater Today 2011; 14:190-195.
28. Schneider D. Using Drosophila as a model insect. Nat Rev Genet 2000;1: 218-226.
29. Pandey UB. and Nichols CD. Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacol Rev 2011;63, 411-436.
30. Graf U, Würgler FE, Katz, A.J. et al. Somatic mutation test in Drosophila melanogaster. Environmental and Molecular Mutagenesis 1984; 6, 153-188.
31. Lewis, E.B. and Bacher, F. Methods of feeding ethylmethanesulfonate (EMS) to Drosophila males. Drosophila Information Service 1968; 43, 193.
32. Zordan M, Osti M, Pesce M, Costa R. Chloral hydrate is recombinogenic in the wing spot test in Drosophila melanogaster. Mutat. Res 1994;322, 111-116.
33. Negishi T, Negishi K, Ryo H, Kando S, Hayatsu S. The genotoxicity of N4-aminocytidine in the Drosophila wing spot test. Mutagenesis 1988; 3 (1), 11-13.
34. Schaik VN. and Graf U. Genotoxicity evaluation of five tricyclic antidepressant in the wing somatic mutation and recombination test in D. melanogaster. Mutat. Res 1991;260, 99-104.
35. Frei H. and Würgler FE. Statistical methods to decide whether mutagenicity test data from Drosophila assays indicate a positive, negative, or inconclusive result. Mutat Res Environ Mutagen Relat Subj 1988; 203(4), 297-308.
36. Frei H, Würgler FE. Optimal experimental design and sample size for the statistical evaluation of data from somatic mutation and recombination tests (SMART) in Drosophila. Mutation Research/Environmental Mutagenesis and Related Subjects 1995; 334(2), 247-258.
37. Kastenbaum MA, Bowman KO. Tables for determining the statistical significance of mutation frequencies. Mutation Research 1970; 9, 527-49.
38. Spanó MA, Frei H, Würgler FE, Graf U. Recombinagenic activity of four compounds in the standard and high bioactivation crosses of Drosophila melanogaster in the wing spot test. Mutagenesis 2001; 16(5), 385-394.
39. Matalon ST, Ornoy, A, Lishner M. Review of the potential effects of three commonly used antineoplastic and immunosuppressive drugs (cyclophosphamide, azathioprine, doxorubicin on the embryo and placenta), Reprod Toxicol 2004; 18(2), 219-230.
40. Anderson D, Bishop JB, Garner RC, Ostrosky-Wegman P, Selby PB. Cyclophosphamide: review of its mutagenicity for an assessment of potential germ cell risks. Mutat Res Fund Mol Mech Mutagen 1995; 330(1), 115-181.
41. Kumar KBH, Kuttan R. Chemoprotective Activity of an Extract of Phyllanthus amarus Against Cyclophosphamide Induced Toxicity in Mice. Phytomedicine, 2004; 12: 494-500.
42. Abraham P, Isaac B. Ultrastructural changes in the rat kidney after single dose of cyclophosphamide—possible roles for peroxisome proliferation and lysosomal dysfunction in cyclophosphamide-induced renal damage. Hum Exp Toxicol 2011; 30(12), 1924-1930.
43. Spanó, MA, Frei H, Würgler FE, Graf U. Recombinagenic activity of four compounds in the standard and high bioactivation crosses of Drosophila melanogaster in the wing spot test. Mutagenesis, 2001; 16(5), 385-394.
44. Kawabata TT, Chapman MY, Kim DH, Stevens WD, Holsapple MP. Mechanism of in vitro Immunosuppression by Hepatocyte Generated Cyclophosphamide Metabolites and 4–Hydroxicyclophosphamide. Biochemical Pharmacology 1990; Vol. 40: No. 5, pp. 927 – 935.
45. Senthilkumar S, Devaki T, Manohar BM, Babu MS. Effect of squalene on cyclophosphamide-induced toxicity. Clinica Chimica Acta, International Journal of Clinical Chemistry 2006; 364: 335-342.
46. Eleazu CO, Eleazu KC, Chukwuma S, Essien UN. Review of the mechanism of cell death resulting from streptozotocin challenge in experimental animals, its practical use and potential risk to humans. J Diabetes Metab Disord 2013; 12(1), 60.
47. Coskun O, Kanter M, Korkmaz A, Oter S. Quercetin, a flavonoid antioxidant, prevents and protects streptozotocin-induced oxidative stress and β-cell damage in rat pancreas. Pharmacol Res 2005; 51(2), 117-123.
48. Fernández-Bedmar Z, Anter J, de La Cruz-Ares S, Muñoz-Serrano A, Alonso-Moraga Á, Pérez-Guisado J. Role of citrus juices and distinctive components in the modulation of degenerative processes: genotoxicity, antigenotoxicity, cytotoxicity, and longevity in Drosophila. J Toxicol Environ Health, Part A 2011; 74(15-16), 1052-1066.
49. Romero-Jiménez M, Campos-Sánchez J, Analla M, Muñoz-Serrano A, Alonso-Moraga Á. Genotoxicity and anti-genotoxicity of some traditional medicinal herbs. Mutation Research/Genetic Toxicology and Environmental Mutagenesis 2005; 585(1), 147-155.
50. Demir E, Kocaoğlu S, Çetin H, Kaya B. Antigenotoxic effects of Citrus aurentium L. fruit peel oil on mutagenicity of two alkylating agents and two metals in the Drosophila wing spot test. Environ. Mol. Mut. 2009; 50, 483-488
51. Idaomar M, El Hamss R, Bakkali F. et al. Genotoxicity and antigenotoxicity of some essential oils evaluated by wing spot test of Drosophila melanogaster. Mutat. Res 2002; 513, 61-68.
52. Kızılet H, Kasimoğlu C, Uysal H. Can the Rosa canina plant be used against alkylating agents as a radical scavenger. Pol J Environ Stud 2013; 22, 1263-1267.
53. Valadares BLB, Graf U, Spano M.A. Inhibitory effects of water extract of propolis on doxorubicin-induced somatic mutation and recombination in Drosophila melanogaster. Food Chem Toxicol 2007; 46, 1103–1110.
54. Demir E. Kaya B, Marcos R, Cenkçi SK, Çetin H. Investigation of the genotoxic and antigenotoxic properties of essential oils obtained from two Origanum species by Drosophila wing SMART assay. Turkish Journal of Biology 2013; 37(2), 129-138.
55. Patenkovic A, Stamenkovic-Radak M, Banjanac T, Andjelkovic M. Antimutagenic effect of sage tea in the wing spot test of Drosophila melanogaster. Food Chem Toxicol 2009; 47(1), 180-183.
56. de Rezende AAA, Graf U, da Rosa Guterres Z, Kerr WE, Spanó MA. Protective effects of proanthocyanidins of grape (Vitis vinifera L.) seeds on DNA damage induced by Doxorubicin in somatic cells of Drosophila melanogaster. Food Chem Toxicol 2009; 47(7), 1466-1472.
57. Demir E, Kocaoğlu S, Kaya B. Antigenotoxic properties of chlorophyllin and chlorophylls in the Drosophila wing spot test. Fresen Environ Bull 2010; 19(12), 3131-3138.
58. Demir E, Kocaoğlu S, Çetin H. Kaya B. Antigenotoxic effects of Citrus aurentium L. fruit peel oil on mutagenicity of two alkylating agents and two metals in the Drosophila wing spot test. Environ Mol Mutagen 2009; 50(6), 483-488.
59. Fernandes, LM, Guterres ZR, Almeida IV, Vicentini VEP. Genotoxicity and Antigenotoxicity Assessments of the Flavonoid Vitexin by the Drosophila melanogaster Somatic Mutation and Recombination Test. Journal of food 2017; 1–9.
60. Carmona ER, Diaz MR, Parodi J, Blancheteau I.B. Antimutagenic evaluation of traditional medicinal plants from South America Peumus boldus and Cryptocarya alba using Drosophila melanogaster. J Toxicol Environ Health, Part A 2017; 1087-2620.
61. Prakash G, Hosetti BB, Dhananjaya BL. Antimutagenic effect of Dioscorea Pentaphylla on genotoxic effect induced by methyl methanesulfonate in the Drosophila wing spot test. Toxicol Int, 2014; 21(3), 258.
62. Sharangi A. Medicinal and therapeutic potentialities of tea (Camellia sinensis L.)–A review. Food Res Int 2009; 42(5):529-535.
63. Almajano MP, Carbo R, Jiménez J, Gordon M.H. Antioxidant and antimicrobial activities of tea infusions. Food Chem, 2008; 108(1): 55-63.
64. Alarcón E, Campos AM, Edwards AM, Lissi E, López-Alarcón C. Antioxidant capacity of herbal infusions and tea extracts: A comparison of ORAC-fluorescein and ORAC-pyrogallol red methodologies. Food Chem 2008; 107(3), 1114-1119.
65. Vinson JA, Dabbagh YA. Tea Phenols: Antioxidant Effectiveness of Teas, Tea Components, Tea Fractions and Their Binding With Lipoproteins. Nutr Res, 1998; 18: 1067- 1075.
66. Hayatsu H, Inada N, Kakutani T, Arimoto S, Negishi T, Mori K., Sakata I. Suppression of genotoxicity of carcinogens by (−)-epigallocatechin gallate. Prev Med, 1992; 21(3),370-376.
67. Min KJ, Kwon TK. Anticancer effects and molecular mechanisms of epigallocatechin-3-gallate. Integrative Medicine Research 2014; 3(1), 16-24.
68. Mao JT, Nie WX, Tsu IH. et al. White tea extract induces apoptosis in non–small cell lung cancer cells: the role of peroxisome proliferator-activated receptor-γ and 15-lipoxygenases. Canc Prev Res 2010;3(9), 1132-1140.
69. Camouse MM, Domingo DS, Swain, F.R. et al. Topical application of green and white tea extracts provides protection from solar‐simulated ultraviolet light in human skin. Exp Dermatol 2009; 18(6), 522-526,
70. Santana-Rios G, Orner GA, Amantana A, Provost C, Wu SY, Dashwood RH. Potent antimutagenic activity of white tea in comparison with green tea in the Salmonella assay. Mutat Res Genet Toxicol Environ Mutagen 2001; 495(1), 61-74.
71. Espinosa C, Pérez-Llamas F, Guardiola FA. et al. Molecular mechanisms by which white tea prevents oxidative stress. J Physiol Biochem, 2014; 70(4), 891-900.
72. Espinosa C, López-Jiménez, JÁ, Cabrera L, Larqué E, Almajano MP, Arnao MB, Pérez-Llamas F. Protective effect of white tea extract against acute oxidative injury caused by adriamycin in different tissues. Food Chem 2012; 134(4), 1780-1785.
73. Mitra DK, Shah PM, Shah HH, Rodrigues SV, Mehta CJ. The antiplaque efficacy of white tea extract mouthrinse. J Indian Soc Periodontol 2017; 1, 1-4.
74. Zhao L, La VD, Grenier D. Antibacterial, antiadherence, antiprotease, and anti-inflammatory activities of various tea extracts: potential benefits for periodontal diseases. Journal of medicinal food 2013; 16 (5), 428-436.
75. Vanka A, Vanka S. White tea: A contributor to oral health. DRJ 2012; 9(4), 504.
76. Enzveiler L, Gressler G, Heckler E, Picoli S, Suyenaga, ES. Evaluation of antimicrobial activity of aqueous extract of white tea Camellia sinensis L. Kuntze (1887). Pharmacologia 2011; 2(5):131–136.
77. Abdella EMM. Protective Effects Of White Tea Extract Against Mercuric Chloride Induced Hepatotoxicity in Mice. Int J Pharmaceut Sci Res 2017; 8(2), 603.