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In vitro Evaluation of Antigenotoxic Effects of Phloridzin

Year 2022, Volume 43, Issue 3, 358 - 364, 30.09.2022
https://doi.org/10.17776/csj.1035449

Abstract

Phytochemicals have a vast number of properties contributing to human health by acting on numerous different mechanisms. Phloridzin, a phytochemical mainly found in Malus species, possesses diverse biological activities including anti-diabetic and antioxidative activities. Here, our aim is to explore antigenotoxic potential and proliferative effects of phloridzin on human lymphocytes in vitro by employing chromosome aberration, micronucleus and comet assays. Mitomycin C, both an anticancer and genotoxic agent, was utilized to induce genotoxicity. Phloridzin significantly suppressed the genotoxic effects of mitomycin C at 125-500 µg/mL concentrations in all assays used (p < 0.05). We also revealed that phloridzin and mitomycin C combination had a significantly negative effect on mitotic index (p < 0.05), whereas in general, gender differences did not play a role in manifestation of neither antigenotoxic nor antiproliferative activities of the combination.These results suggest that phloridzin is an antigenotoxic compound and its consumption may interfere with the activity of anticancer drugs that exert their effects based on genotoxic mechanisms.

References

  • [1] Zhang L., Virgous C., Si H., Synergistic anti–inflammatory effects and mechanisms of combined phytochemicals, J. Nutr. Biochem., 69 (2019) 19–30.
  • [2] Chikara S., Nagaprashantha L.D., Singhal J., Horne D., Awasthi S., Singhal S.S., Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment, Cancer Lett., 413 (2018) 122–134.
  • [3] Zhang Y.J., Gan R.Y., Li S., Zhou Y., Li A.N., Xu D.P., Li H.B., Antioxidant phytochemicals for the prevention and treatment of chronic diseases, Molecules, 20 (12) 2015 21138–21156.
  • [4] Dembinska-Kiec A., Mykkänen O., Kiec-Wilk B., Mykkänen H., Antioxidant phytochemicals against type 2 diabetes, Br. J. Nutr., 99 (E-S1), 2008, ES109–ES117.
  • [5] Gosch C., Halbwirth H., Stich K., Phloridzin: biosynthesis, distribution and physiological relevance in plants, Phytochemistry, 71 (2010) 838–843.
  • [6] Hilt P., Schieber A., Yildirim C., Arnold G., Klaiber I., Conrad J., Beifuss U., Carle R., Detection of phloridzin in strawberries (Fragaria x ananassa Duch.) by HPLC–PDA–MS/MS and NMR spectroscopy, J. Agric. Food. Chem., 51 (2003) 2896–2899.
  • [7] Cox S.D., Jayasinghe K.C., Markham J.L., Antioxidant activity in Australian native sarsaparilla (Smilax glyciphylla), J. Ethnopharmacol., 101 (2005) 162–168.
  • [8] Dong H., Ning Z., Yu L., Li L., Lin L., Huang J., Preparative separation and identification of the flavonoid phlorhizin from the crude extract of Lithocarpus polystachyus Rehd, Molecules, 12 (2007) 552–562.
  • [9] Baldisserotto A., Malisardi G., Scalambra E., Andreotti E., Romagnoli C., Vicentini C.B., Manfredini S., Vertuani S., Synthesis, antioxidant and antimicrobial activity of a new phloridzin derivative for dermo–cosmetic applications, Molecules, 17 (11) (2012) 13275–13289.
  • [10] Ehrenkranz J.R., Lewis N.G., Kahn C.R., Roth J., Phlorizin: A review, Diabetes Metab. Res. Rev., 21 (2005) 31–38.
  • [11] David–Silva A., Esteves J.V., Morais M.R.P., Freitas H.S., Zorn T.M., Correa–Giannella M.L., Machado U.F., Dual SGLT1/SGLT2 inhibitor phlorizin ameliorates non–alcoholic fatty liver disease and hepatic glucose production in type 2 diabetic mice, Diabetes Metab. Syndr. Obes., 13 (2020) 739–751.
  • [12] Rezk B.M., Haenen G.R., van der Vijgh W.J., Bast A., The antioxidant activity of phloretin: the disclosure of a new antioxidant pharmacophore in flavonoids, Biochem. Biophys. Res. Commun., 295 (1) (2002) 9–13.
  • [13] Chang W.T., Huang W.C., Liou C.J., Evaluation of the anti–inflammatory effects of phloretin and phlorizin in lipopolysaccharide–stimulated mouse macrophages, Food Chem., 134 (2) (2012) 972–979.
  • [14] Hirose M., Shibazaki T., Nakada T., Kashihara T., Yano S., Okamoto Y., Isaji M., Matsushita N., Taira E., Yamada M., Phlorizin prevents electrically–induced ventricular tachyarrhythmia during ischemia in langendorff–perfused guinea–pig hearts, Biol. Pharm. Bull., 37 (7) (2014) 1168–1176.
  • [15] Khalifa M.M., Bakr A.G., Osman A.T., Protective effects of phloridzin against methotrexate–induced liver toxicity in rats, Biomed. Pharmacother., 95 (2017) 529–535.
  • [16] Kaya F.F., Topaktaş M., Genotoxic effects of potassium bromate on human peripheral lymphocytes in vitro, Mutat. Res. - Genet. Toxicol. Environ. Mutagen., 626 (1–2) (2007) 48–52.
  • [17] IPCS, Guide to Short Term Tests for Detecting Mutagenic and Carcinogenic Chemicals, Geneva: World Health Organization, (1985).
  • [18] Fenech M., Morley A.A., Measurement of micronuclei in lymphocytes, Mutat. Res. Genet. Toxicol. Environ. Mutagen., 147(1–2) (1985) 29–36.
  • [19] Singh N.P., McCoy M.T., Tice R.R., Schneider E.L., A simple technique for quantitation of low levels of DNA damage in individual cells, Exp. Cell Res., 175 (1988) 184–191.
  • [20] Anderson D., Yu T.W., Phillips B.J., Schmezer P., The effect of various antioxidants and other modifying agents on oxygen–radical–generated DNA damage in human lymphocytes in the COMET assay, Mutat. Res., 307 (1994) 261–271.
  • [21] Jamshidi–Kia F., Lorigooini Z., Amini–Khoei H., Medicinal plants: Past history and future perspective, J. HerbMed Pharmacol., 7 (1) (2018) 1–7.
  • [22] Hyson D.A., A comprehensive review of apples and apple components and their relationship to human health, Adv. Nutr., 2 (5) (2011) 408–420.
  • [23] Handan B.A., De Moura C.F.G., Cardoso C.M., Santamarina A.B., Pisani L.P., Ribeiro D.A., Protective Effect of Grape and Apple Juices against Cadmium Intoxication in the Kidney of Rats, Drug Res., 70 (11) (2020) 503–511.
  • [24] Vasantha Rupasinghe H.P., Yasmin A., Inhibition of oxidation of aqueous emulsions of omega–3 fatty acids and fish oil by phloretin and phloridzin, Molecules, 15 (1) (2010) 251–257.
  • [25] Cao J., Jiang L.P., Liu Y., Yang G., Yao X.F., Zhong L.F., Curcumin–induced genotoxicity and antigenotoxicity in HepG2 cells, Toxicon, 49 (8) (2007) 1219–1222.
  • [26] Erdem M.G., Cinkilic N., Vatan O., Yilmaz D., Bagdas D., Bilaloglu R., Genotoxic and anti–genotoxic effects of vanillic acid against mitomycin C–induced genomic damage in human lymphocytes in vitro, Asian Pac. J. Cancer Prev., 13 (10) (2012) 4993–4998.
  • [27] Błasiak J., Trzeciak A., Dziki A., Ulańska J., Pander B., Synergistic Effect of Vitamin C on DNA Damage Induced by Cadmium, Gen. Physiol. Biophys., 19 (4) (2000) 373–379.
  • [28] [28] Fox J.T., Sakamuru S., Huang R., Teneva N., Simmons S.O., Xia M., Tice R.R., Austin C.P., Myung K., High-throughput genotoxicity assay identifies antioxidants as inducers of DNA damage response and cell death, Proc. Natl. Acad. Sci. U.S.A., 109 (14), 2012, 5423–5428.
  • [29] Lu L.Y., Ou N., Lu Q.B., Antioxidant induces DNA damage, cell death and mutagenicity in human lung and skin normal cells, Sci. Rep., 3(1) 2013 1–11.
  • [30] Verweij J., Pinedo H.M., Mitomycin C: mechanism of action, usefulness and limitations, Anticancer Drugs, 1 (1) (1990) 5–13.
  • [31] Choy W.N., Genetic toxicology and cancer risk assessment, New York: Marcel Dekker, Inc., (2001).
  • [32] Preston R.J., Dean B.J., Galloway S., Holden H., McFee A.F., Shelby M., Mammalian in vivo cytogenetic assays: Analysis of chromosome aberrations in bone marrow cells, Mutat. Res., 189 (1987) 157–165.
  • [33] Kirsch–Volders M., Elhajouji A., Cundari E., Van Hummelen P., The in vitro micronucleus test: a multi–endpoint assay to detect simultaneously mitotic delay, apoptosis, chromosome breakage, chromosome loss and non–disjunction, Mutat. Res. Genet. Toxicol. Environ. Mutagen., 392(1–2) (1997) 19–30.
  • [34] D'Costa A., Kumar M.P., Shyama S.K., Genotoxicity Assays: The Micronucleus Test and the Single–cell Gel Electrophoresis Assay. In: Meena S.N., Naik M.M., (Eds). Advances in Biological Science Research. Cambridge: Academic Press, (2019) 291–301.
  • [35] Sun L., Sun J., Thavaraj P., Yang X., Guo Y., Effects of thinned young apple polyphenols on the quality of grass carp (Ctenopharyngodon idellus) surimi during cold storage, Food Chem., 224 (2017) 372–381.
  • [36] Cheng K.W., Wu Q., Zheng Z.P., Peng X., Simon J.E., Chen F., Wang M., Inhibitory effect of fruit extracts on the formation of heterocyclic amines, J. Agric. Food Chem., 55 (25) (2007) 10359–10365.
  • [37] Shao X., Bai N., He K., Ho C.T., Yang C.S., Sang S., Apple polyphenols, phloretin and phloridzin: New trapping agents of reactive dicarbonyl species, Chem. Res. Toxicol., 21 (10) (2008) 2042–2050.
  • [38] Lee J., Jung E., Kim Y.S., Park D., Toyama K., Date A., Lee J., Phloridzin isolated from Acanthopanax senticosus promotes proliferation of α6 integrin (CD 49f) and β1 integrin (CD29) enriched for a primary keratinocyte population through the ERK–mediated mTOR pathway, Arch. Dermatol. Res., 305 (8) (2013) 747–754.
  • [39] Aliyu M., Odunola O.A., Farooq A.D., Mesaik A.M., Choudhary M.I., Azhar M., Asif M.M., Erukainure O.L., Antioxidant, mitogenic and immunomodulatory potentials of acacia honey, Nutr. Ther. Metab., 32 (2) (2014) 68–78.
  • [40] Avuloglu–Yilmaz E., Yuzbasioglu D., Unal F., In vitro genotoxicity assessment of monopotassium glutamate and magnesium diglutamate, Toxicol. In Vitro, 65 (2020) 104780.

Year 2022, Volume 43, Issue 3, 358 - 364, 30.09.2022
https://doi.org/10.17776/csj.1035449

Abstract

References

  • [1] Zhang L., Virgous C., Si H., Synergistic anti–inflammatory effects and mechanisms of combined phytochemicals, J. Nutr. Biochem., 69 (2019) 19–30.
  • [2] Chikara S., Nagaprashantha L.D., Singhal J., Horne D., Awasthi S., Singhal S.S., Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment, Cancer Lett., 413 (2018) 122–134.
  • [3] Zhang Y.J., Gan R.Y., Li S., Zhou Y., Li A.N., Xu D.P., Li H.B., Antioxidant phytochemicals for the prevention and treatment of chronic diseases, Molecules, 20 (12) 2015 21138–21156.
  • [4] Dembinska-Kiec A., Mykkänen O., Kiec-Wilk B., Mykkänen H., Antioxidant phytochemicals against type 2 diabetes, Br. J. Nutr., 99 (E-S1), 2008, ES109–ES117.
  • [5] Gosch C., Halbwirth H., Stich K., Phloridzin: biosynthesis, distribution and physiological relevance in plants, Phytochemistry, 71 (2010) 838–843.
  • [6] Hilt P., Schieber A., Yildirim C., Arnold G., Klaiber I., Conrad J., Beifuss U., Carle R., Detection of phloridzin in strawberries (Fragaria x ananassa Duch.) by HPLC–PDA–MS/MS and NMR spectroscopy, J. Agric. Food. Chem., 51 (2003) 2896–2899.
  • [7] Cox S.D., Jayasinghe K.C., Markham J.L., Antioxidant activity in Australian native sarsaparilla (Smilax glyciphylla), J. Ethnopharmacol., 101 (2005) 162–168.
  • [8] Dong H., Ning Z., Yu L., Li L., Lin L., Huang J., Preparative separation and identification of the flavonoid phlorhizin from the crude extract of Lithocarpus polystachyus Rehd, Molecules, 12 (2007) 552–562.
  • [9] Baldisserotto A., Malisardi G., Scalambra E., Andreotti E., Romagnoli C., Vicentini C.B., Manfredini S., Vertuani S., Synthesis, antioxidant and antimicrobial activity of a new phloridzin derivative for dermo–cosmetic applications, Molecules, 17 (11) (2012) 13275–13289.
  • [10] Ehrenkranz J.R., Lewis N.G., Kahn C.R., Roth J., Phlorizin: A review, Diabetes Metab. Res. Rev., 21 (2005) 31–38.
  • [11] David–Silva A., Esteves J.V., Morais M.R.P., Freitas H.S., Zorn T.M., Correa–Giannella M.L., Machado U.F., Dual SGLT1/SGLT2 inhibitor phlorizin ameliorates non–alcoholic fatty liver disease and hepatic glucose production in type 2 diabetic mice, Diabetes Metab. Syndr. Obes., 13 (2020) 739–751.
  • [12] Rezk B.M., Haenen G.R., van der Vijgh W.J., Bast A., The antioxidant activity of phloretin: the disclosure of a new antioxidant pharmacophore in flavonoids, Biochem. Biophys. Res. Commun., 295 (1) (2002) 9–13.
  • [13] Chang W.T., Huang W.C., Liou C.J., Evaluation of the anti–inflammatory effects of phloretin and phlorizin in lipopolysaccharide–stimulated mouse macrophages, Food Chem., 134 (2) (2012) 972–979.
  • [14] Hirose M., Shibazaki T., Nakada T., Kashihara T., Yano S., Okamoto Y., Isaji M., Matsushita N., Taira E., Yamada M., Phlorizin prevents electrically–induced ventricular tachyarrhythmia during ischemia in langendorff–perfused guinea–pig hearts, Biol. Pharm. Bull., 37 (7) (2014) 1168–1176.
  • [15] Khalifa M.M., Bakr A.G., Osman A.T., Protective effects of phloridzin against methotrexate–induced liver toxicity in rats, Biomed. Pharmacother., 95 (2017) 529–535.
  • [16] Kaya F.F., Topaktaş M., Genotoxic effects of potassium bromate on human peripheral lymphocytes in vitro, Mutat. Res. - Genet. Toxicol. Environ. Mutagen., 626 (1–2) (2007) 48–52.
  • [17] IPCS, Guide to Short Term Tests for Detecting Mutagenic and Carcinogenic Chemicals, Geneva: World Health Organization, (1985).
  • [18] Fenech M., Morley A.A., Measurement of micronuclei in lymphocytes, Mutat. Res. Genet. Toxicol. Environ. Mutagen., 147(1–2) (1985) 29–36.
  • [19] Singh N.P., McCoy M.T., Tice R.R., Schneider E.L., A simple technique for quantitation of low levels of DNA damage in individual cells, Exp. Cell Res., 175 (1988) 184–191.
  • [20] Anderson D., Yu T.W., Phillips B.J., Schmezer P., The effect of various antioxidants and other modifying agents on oxygen–radical–generated DNA damage in human lymphocytes in the COMET assay, Mutat. Res., 307 (1994) 261–271.
  • [21] Jamshidi–Kia F., Lorigooini Z., Amini–Khoei H., Medicinal plants: Past history and future perspective, J. HerbMed Pharmacol., 7 (1) (2018) 1–7.
  • [22] Hyson D.A., A comprehensive review of apples and apple components and their relationship to human health, Adv. Nutr., 2 (5) (2011) 408–420.
  • [23] Handan B.A., De Moura C.F.G., Cardoso C.M., Santamarina A.B., Pisani L.P., Ribeiro D.A., Protective Effect of Grape and Apple Juices against Cadmium Intoxication in the Kidney of Rats, Drug Res., 70 (11) (2020) 503–511.
  • [24] Vasantha Rupasinghe H.P., Yasmin A., Inhibition of oxidation of aqueous emulsions of omega–3 fatty acids and fish oil by phloretin and phloridzin, Molecules, 15 (1) (2010) 251–257.
  • [25] Cao J., Jiang L.P., Liu Y., Yang G., Yao X.F., Zhong L.F., Curcumin–induced genotoxicity and antigenotoxicity in HepG2 cells, Toxicon, 49 (8) (2007) 1219–1222.
  • [26] Erdem M.G., Cinkilic N., Vatan O., Yilmaz D., Bagdas D., Bilaloglu R., Genotoxic and anti–genotoxic effects of vanillic acid against mitomycin C–induced genomic damage in human lymphocytes in vitro, Asian Pac. J. Cancer Prev., 13 (10) (2012) 4993–4998.
  • [27] Błasiak J., Trzeciak A., Dziki A., Ulańska J., Pander B., Synergistic Effect of Vitamin C on DNA Damage Induced by Cadmium, Gen. Physiol. Biophys., 19 (4) (2000) 373–379.
  • [28] [28] Fox J.T., Sakamuru S., Huang R., Teneva N., Simmons S.O., Xia M., Tice R.R., Austin C.P., Myung K., High-throughput genotoxicity assay identifies antioxidants as inducers of DNA damage response and cell death, Proc. Natl. Acad. Sci. U.S.A., 109 (14), 2012, 5423–5428.
  • [29] Lu L.Y., Ou N., Lu Q.B., Antioxidant induces DNA damage, cell death and mutagenicity in human lung and skin normal cells, Sci. Rep., 3(1) 2013 1–11.
  • [30] Verweij J., Pinedo H.M., Mitomycin C: mechanism of action, usefulness and limitations, Anticancer Drugs, 1 (1) (1990) 5–13.
  • [31] Choy W.N., Genetic toxicology and cancer risk assessment, New York: Marcel Dekker, Inc., (2001).
  • [32] Preston R.J., Dean B.J., Galloway S., Holden H., McFee A.F., Shelby M., Mammalian in vivo cytogenetic assays: Analysis of chromosome aberrations in bone marrow cells, Mutat. Res., 189 (1987) 157–165.
  • [33] Kirsch–Volders M., Elhajouji A., Cundari E., Van Hummelen P., The in vitro micronucleus test: a multi–endpoint assay to detect simultaneously mitotic delay, apoptosis, chromosome breakage, chromosome loss and non–disjunction, Mutat. Res. Genet. Toxicol. Environ. Mutagen., 392(1–2) (1997) 19–30.
  • [34] D'Costa A., Kumar M.P., Shyama S.K., Genotoxicity Assays: The Micronucleus Test and the Single–cell Gel Electrophoresis Assay. In: Meena S.N., Naik M.M., (Eds). Advances in Biological Science Research. Cambridge: Academic Press, (2019) 291–301.
  • [35] Sun L., Sun J., Thavaraj P., Yang X., Guo Y., Effects of thinned young apple polyphenols on the quality of grass carp (Ctenopharyngodon idellus) surimi during cold storage, Food Chem., 224 (2017) 372–381.
  • [36] Cheng K.W., Wu Q., Zheng Z.P., Peng X., Simon J.E., Chen F., Wang M., Inhibitory effect of fruit extracts on the formation of heterocyclic amines, J. Agric. Food Chem., 55 (25) (2007) 10359–10365.
  • [37] Shao X., Bai N., He K., Ho C.T., Yang C.S., Sang S., Apple polyphenols, phloretin and phloridzin: New trapping agents of reactive dicarbonyl species, Chem. Res. Toxicol., 21 (10) (2008) 2042–2050.
  • [38] Lee J., Jung E., Kim Y.S., Park D., Toyama K., Date A., Lee J., Phloridzin isolated from Acanthopanax senticosus promotes proliferation of α6 integrin (CD 49f) and β1 integrin (CD29) enriched for a primary keratinocyte population through the ERK–mediated mTOR pathway, Arch. Dermatol. Res., 305 (8) (2013) 747–754.
  • [39] Aliyu M., Odunola O.A., Farooq A.D., Mesaik A.M., Choudhary M.I., Azhar M., Asif M.M., Erukainure O.L., Antioxidant, mitogenic and immunomodulatory potentials of acacia honey, Nutr. Ther. Metab., 32 (2) (2014) 68–78.
  • [40] Avuloglu–Yilmaz E., Yuzbasioglu D., Unal F., In vitro genotoxicity assessment of monopotassium glutamate and magnesium diglutamate, Toxicol. In Vitro, 65 (2020) 104780.

Details

Primary Language English
Subjects Biology
Journal Section Natural Sciences
Authors

Mehmet SARİMAHMUT> (Primary Author)
BURSA ULUDAĞ ÜNİVERSİTESİ, FEN-EDEBİYAT FAKÜLTESİ, BİYOLOJİ BÖLÜMÜ
0000-0003-2647-5875
Türkiye


Sindi VEKSHARİ This is me
BURSA ULUDAĞ ÜNİVERSİTESİ, FEN-EDEBİYAT FAKÜLTESİ
0000-0001-7975-3950
Türkiye


Merve DEMİRBAG KARAALİ This is me
BURSA ULUDAĞ ÜNİVERSİTESİ, FEN-EDEBİYAT FAKÜLTESİ
0000-0002-2874-0241
Türkiye


Serap CELİKLER This is me
BURSA ULUDAĞ ÜNİVERSİTESİ, FEN-EDEBİYAT FAKÜLTESİ
0000-0002-4177-3478
Türkiye

Thanks The authors would like to thank Ahmet Sari Mahmout for English editing and proofreading of the manuscript.
Publication Date September 30, 2022
Application Date December 14, 2021
Acceptance Date August 27, 2022
Published in Issue Year 2022, Volume 43, Issue 3

Cite

APA Sarimahmut, M. , Vekshari, S. , Demirbag Karaali, M. & Celikler, S. (2022). In vitro Evaluation of Antigenotoxic Effects of Phloridzin . Cumhuriyet Science Journal , 43 (3) , 358-364 . DOI: 10.17776/csj.1035449