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In vitro Evaluation of Antigenotoxic Effects of Phloridzin

Yıl 2022, Cilt: 43 Sayı: 3, 358 - 364, 30.09.2022

Mehmet Sarimahmut , Sindi Vekshari Merve Demirbag Karaali Serap Celikler

https://doi.org/10.17776/csj.1035449

Öz

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.

Anahtar Kelimeler

Phlorizin Genotoxicity Mitomycin C Chromosome aberration.

Teşekkür

The authors would like to thank Ahmet Sari Mahmout for English editing and proofreading of the manuscript.

Kaynakça

  • [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.

Yıl 2022, Cilt: 43 Sayı: 3, 358 - 364, 30.09.2022

Mehmet Sarimahmut , Sindi Vekshari Merve Demirbag Karaali Serap Celikler

https://doi.org/10.17776/csj.1035449

Öz

Kaynakça

  • [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.
Toplam 40 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Yapısal Biyoloji
Bölüm Natural Sciences
Yazarlar

Mehmet Sarimahmut 0000-0003-2647-5875

Sindi Vekshari 0000-0001-7975-3950

Merve Demirbag Karaali 0000-0002-2874-0241

Serap Celikler 0000-0002-4177-3478

Yayımlanma Tarihi 30 Eylül 2022
Gönderilme Tarihi 14 Aralık 2021
Kabul Tarihi 27 Ağustos 2022
Yayımlandığı Sayı Yıl 2022Cilt: 43 Sayı: 3

Kaynak Göster

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. https://doi.org/10.17776/csj.1035449
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