Pharmacological Aspects and Potential Use of Phloretin: A Systemic Review

Author(s): Arokia V.A. Mariadoss*, Ramachandran Vinyagam, Vinothkumar Rajamanickam, Vijayalakshmi Sankaran, Sathish Venkatesan, Ernest David*

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 19 , Issue 13 , 2019


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Abstract:

Over the past two decades, many researchers have concluded that a diet rich in polyphenolic compounds plays an important therapeutic role in reducing the risk of cancer, cardiovascular disease, inflammation, diabetes, and other degenerative diseases. Polyphenolic compounds have been reported to be involved in neutralization of reactive oxygen species and charged radicals, and have anticarcinogenic effects, hepatoprotective effects, low-glycaemic response, and other benefits. The benefits of fruits and vegetables may be partly attributable to polyphenolic compounds, which have antioxidant and free radical scavenging properties. Fruits such as apples contain a variety of phytochemicals, including (+)-catechin and (-)-epicatechin, phlorizin, phloretin quercetin, cyanidin-3-Ogalactoside, chlorogenic acid, and p-coumaric acid, all of which are strong antioxidants. Phloretin, a natural phenolic compound, is a dihydrochalcone, which is present in the apple. It exhibits a wide variety of activities such as antioxidative, anti-inflammatory, anti-microbial, anti-allergic, anticarcinogenic, anti-thrombotic, and hepatoprotective, besides being involved in the activation of apoptotic associated gene expression and signal transduction in molecular pathways. Despite a multitude of clinical studies, new efforts are needed in clinical research to determine the complete therapeutic potential of phloretin.

Keywords: Phloretin, antioxidant, anti-inflammatory, anti-microbial, anti-allergic, anti-carcinogenic, anti-thrombotic.

[1]
Kris-Etherton, P.M.; Hecker, K.D.; Bonanome, A.; Coval, S.M.; Binkoski, A.E.; Hilpert, K.F.; Griel, A.E.; Etherton, T.D. Bioactive compounds in foods: Their role in the prevention of cardiovascular disease and cancer. Am. J. Med., 2002, 113, 71-88.
[2]
World Health Organization., WHO STEPS surveillance manual: The WHO stepwise approach to chronic disease risk factor surveillance. 2005.
[3]
Tsao, R.; Yang, R.; Young, J.C.; Zhu, H. Polyphenolic profiles in eight apple cultivars using high-performance liquid chromatography (HPLC). J. Agric. Food Chem., 2003, 51, 6347-6353.
[4]
Escarpa, A.; Gonzalez, M.C. High-performance liquid chromatography with diode-array detection for the determination of phenolic compounds in peel and pulp from different apple varieties. J. Chromatogr., 1998, A823, 331-337.
[5]
Gosch, C.; Halbwirth, H.; Stich, K. Phlorizin: Biosynthesis, distribution and physiological relevance in plants. Phytochemistry, 2010, 71, 838-843.
[6]
Lattanzio, V.; Di Venere, D.; Linsalata, V.; Bertolini, P.; Ippolito, A.; Salerno, M. Low temperature metabolism of apple phenolics and quiescence of Phlyctaena vagabunda. J. Agric. Food Chem., 2001, 49, 5817-5821.
[7]
Auner, B.G.; O’Neill, M.A.; Valenta, C. Interaction of phloretin and 6-ketocholestanol with DPPC-liposomes as phospholipid model membranes. Int. J. Pharm., 2005, 294, 149-155.
[8]
Wei, Y.; Zhang, J.; Memon, A.H.; Liang, H. Molecular model and in vitro antioxidant activity of a water-soluble and stable phloretin/hydroxypropyl-β-cyclodextrin inclusion complex. J. Mol. Liq., 2017, 236, 68-75.
[9]
Wang, H.; Wang, D.; Pu, Y.; Pan, D.; Guan, W.; Ma, Y. Phloretin induced apoptosis of human hepatoma cells SMMC-7721 and its correlative biological mechanisms. Afr. J. Pharm. Pharmacol., 2012, 86, 648-659.
[10]
Stangl, V.; Lorenz, M.; Ludwig, A.; Grimbo, N.; Guether, C.; Sanad, W.; Ziemer, S.; Martus, P.; Baumann, G.; Stangl, K. The flavonoid phloretin suppresses stimulated expression of endothelial adhesion molecules and reduces activation of human platelets. J. Nutr., 2005, 135, 172-178.
[11]
Sherif, M.H.; Abas, A.S.; Abdrabouh, D.S. Anti-tumor activity of phloretin in treatment of hepatocellular induced carcinoma in rats. J. Chem. Pharm. Res., 2017, 9, 82-92.
[12]
Barreca, D.; Bellocco, E.; Lagana, G.; Ginestra, G.; Bisignano, C. Biochemical and antimicrobial activity of phloretin and its glycosilated derivatives present in apple and kumquat. Food Chem., 2014, 160, 292-297.
[13]
Ma, J.; Peng, X.; Ng, K.M.; Che, C.M.; Wang, M. Impact of phloretin and phloridzin on the formation of maillard reaction products in aqueous models composed of glucose and l-lysine or its derivatives. Food Funct., 2012, 3, 178-186.
[14]
Sauceda, A.E.; Sayago‐Ayerdi, S.G.; Fernando, J. Biological actions of phenolic compounds. fruit and vegetable phytochemicals: Chemistry and Human Health, 2nd ed; Wiley & Sons: New York, 2017.
[15]
Zuo, A.R.; Yu, Y.Y.; Shu, Q.L.; Zheng, L.X.; Wang, X.M.; Peng, S.H.; Xie, Y.F.; Cao, S.W. Hepatoprotective effects and antioxidant, antityrosinase activities of phloretin and phloretin isonicotinyl hydrazone. J. Chin. Med. Assoc., 2014, 77, 290-301.
[16]
Leu, S.J.; Lin, Y.P.; Lin, R.D.; Wen, C.L.; Cheng, K.T.; Hsu, F.L.; Lee, M.H. Phenolic constituents of malusdoumeri var. formosanain the field of skin care. Biol. Pharm. Bull., 2006, 29, 740-745.
[17]
Nakamura, Y.; Watanabe, S.; Miyake, N.; Kohno, H.; Osawa, T. Dihydrochalcones evaluation as novel radical scavenging antioxidants. J. Agric. Food Chem., 2003, 51, 3309-3312.
[18]
Huang, W.C.; Da, Y.W.; Peng, H.L.; Kang, C.W.; Kuo, C.Y.; Liou, C.J. Phloretin ameliorates chemokines and ICAM-1 expression via blocking of the NF-κB pathway in the TNF-α-induced HaCaT human keratinocytes. Int. Immunopharmacol., 2015, 27, 32-37.
[19]
Huang, W.C.; Fang, L.W.; Liou, C.J. Phloretin attenuates allergic airway inflammation and oxidative stress in asthmatic mice. Front. Immunol., 2017, 8, 134.
[20]
Aliomrani, M.; Sepand, M.R.; Mirzaei, H.R.; Nekonam, S.; Sabzevari, O. Effects of phloretin on oxidative and inflammatory reaction in rat model of cecal ligation and puncture induced sepsis. DARU J. Pharm. Sci, 2016, 24, 15.
[21]
Lee, J.H.; Regmi, S.C.; Kim, J.A.; Cho, M.H.; Yun, H.; Lee, C.S.; Lee, J. Apple flavonoid phloretin inhibits Escherichia coli O157: H7 biofilm formation and ameliorates colon inflammation in rats. Infect. Immun., 2011, 79, 4819-4827.
[22]
Fordham, J.B.; Razanaqvi, A.; Nares, S. Leukocyte production of inflammatory mediators is inhibited by the antioxidants phloretin, silymarin, hesperetin, and resveratrol. Mediators Inflamm., 2014, 2014, 938712.
[http://dx.doi.org/10.1155/2014/938712]
[23]
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., 2012, 134, 972-979.
[24]
Huang, W.C.; Lai, C.L.; Liang, Y.T.; Hung, H.C.; Liu, H.C.; Liou, C.J. Phloretin attenuates LPS-induced acute lung injury in mice via modulation of the NF-κB and MAPK pathways. Int. Immunopharmacol., 2016, 40, 98-105.
[25]
McInnes, I.B.; Schett, G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet, 2017, 389, 2328-2337.
[26]
Wang, S.P.; Lin, S.C.; Li, S.; Chao, Y.H.; Hwang, G.Y.; Lin, C.C. Potent antiarthritic properties of phloretin in murine collagen-induced arthritis. Evid. Based Complement. Alternat. Med., 2016, 2016, 9831263.
[http://dx.doi.org/10.1155/2016/9831263]
[27]
Feigin, V.L.; Norrving, B.; Mensah, G.A. Global burden of stroke. Circ. Res., 2017, 120, 439-448.
[28]
Eberhardt, M.V.; Lee, C.Y.; Liu, R.H. Nutrition: Antioxidant activity of fresh apples. Nature, 2000, 405, 903-914.
[29]
Malekova, L.; Tomaskova, J.; Novakova, M.; Stefanik, P.; Kopacek, J.; Lakatos, B.; Pastorekova, S.; Krizanova, O.; Breier, A.; Ondrias, K. Inhibitory effect of DIDS, NPPB, and phloretin on intracellular chloride channels. Pflugers Arch., 2007, 455, 349-357.
[30]
Liu, S.; Yuan, Y.; Zhou, Y.; Zhao, M.; Chen, Y.; Cheng, J.; Lu, Y.; Liu, J. Phloretin attenuates hyperuricemia-induced endothelial dysfunction through co-inhibiting inflammation and GLUT9-mediated uric acid uptake. J. Cell. Mol. Med., 2017, 21, 2553-2562.
[31]
Kunnumakkara, A.B.; Padmavathi, G.; Roy, N.K. Fusion Genes and Cancer, 1st ed; World Scientific Publishing Co Pte Ltd: Singapore, 2017.
[32]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics. CA Cancer J. Clin., 2016, 66, 7-30.
[33]
Zhang, L.; Zuo, Z.; Lin, G. Intestinal and hepatic glucuronidation of flavonoids. Mol. Pharm., 2007, 4, 833-845.
[34]
Anand, M.A.; Suresh, K. Biochemical profiling and chemopreventive activity of phloretin on 7,12-dimethylbenz(a)anthracene induced oral carcinogenesis in male golden Syrian hamsters. Toxicol. Int., 2014, 21, 179-185.
[35]
Liu, Y.; Fan, C.; Pu, L.; Wei, C.; Jin, H.; Teng, Y.; Zhao, M.; Yu, A.C.; Jiang, F.; Shu, J.; Li, F. Phloretin induces cell cycle arrest and apoptosis of human glioblastoma cells through the generation of reactive oxygen species. J. Neurooncol., 2016, 128, 217-223.
[36]
Park, S.Y.; Kim, E.J.; Shin, H.K.; Kwon, D.Y.; Kim, M.S.; Surh, Y.J.; Park, J.H.Y. Induction of apoptosis in HT 29 colon cancer cells by phloretin. J. Med. Food, 2007, 10, 581-586.
[37]
Kobori, M.; Shinmoto, H.; Tsushida, T.; Shinohara, K. Phloretin-induced apoptosis in B16 melanoma 4A5 cells by inhibition of glucose transmembrane transport. Cancer Lett., 1997, 119, 207-212.
[38]
Kobori, M.; Iwashita, K.; Shinmoto, H.; Tsushida, T. Phloretin-induced apoptosis in B16 melanoma 4A5 cells and HL60 human leukemia cells. Biosci. Biotechnol. Biochem., 1999, 63, 719-725.
[39]
Zhou, M.; Zheng, J.; Bi, J. Wu.; Lyu, J.; Gao, K. Synergistic inhibition of colon cancer cell growth by a combination of atorvastatin and phloretin. Oncol. Lett., 2018, 15, 1985-1992.
[40]
Ma, L.; Wang, R.; Nan, Y.; Li, W.; Wang, Q.; Jin, F. Phloretin exhibits an anticancer effect and enhances the anticancer ability of cisplatin on non-small cell lung cancer cell lines by regulating expression of apoptotic pathways and matrix metalloproteinases. Int. J. Oncol., 2016, 48, 843-853.
[41]
Devi, M.A.; Das, N.P. In vitro effects of natural plant polyphenols on the proliferation of normal and abnormal human lymphocytes and their secretions of interleukin-2. Cancer Lett., 1993, 69, 191-196.
[42]
Nelson, J.A.; Falk, R.E. Phloridzin and phloretin inhibition of 2-deoxy-D-glucose uptake by tumor cells in vitro and in vivo. Anticancer Res., 1993, 13, 2293-2299.
[43]
Lu, M.; Kong, Q.; Xu, X.; Lu, H.; Lu, Z.; Yu, W.; Zuo, B.; Su, J.; Guo, R. Evaluation of apoptotic and growth inhibitory activity of phloretin in BGC823 gastric cancer cell. Trop. J. Pharm. Res., 2015, 14, 27-31.
[44]
Zhu, S.P.; Liu, G.; Wu, X.T.; Chen, F.X.; Liu, J.Q.; Zhou, Z.H.; Zhang, J.F.; Fei, S.J. The effect of phloretin on human γδ T cells killing colon cancer SW-1116 cells. Int. Immunopharmacol., 2013, 15, 6-14.
[45]
Yang, K.C.; Tsai, C.Y.; Wang, Y.J.; Lee, C.H.; Chen, J.H.; Wu, C.H. Apple polyphenol phloretin potentiates the anticancer actions of paclitaxel through induction of apoptosis in human hepG2 cells. Mol. Carcinog., 2009, 48, 420-431.
[46]
Choi, B.M.; Chen, X.Y.; Gao, S.S.; Zhu, R.; Kim, B.R. Anti-apoptotic effect of phloretin on cisplatin-induced apoptosis in HEI-OC1 auditory cells. Pharmacol. Rep., 2011, 63, 708-716.
[47]
Przybylska, K.; Bennett, R.N.; Kromer, K.; Gee, J.M. Assessment of the antiproliferative activity of carrot and apple extracts. Pol. J. Food Nutr. Sci., 2007, 57, 307-314.
[48]
Abkin, S.V.; Ostroumova, O.S.; Komarova, E.Y.; Meshalkina, D.A.; Shevtsov, M.A.; Margulis, B.A.; Guzhova, I.V. Phloretin increases the anti-tumor efficacy of intratumorally delivered heat-shock protein 70 kDa (HSP70) in a murine model of melanoma. Cancer Immunol. Immunother., 2016, 65, 83-92.
[49]
Wang, G.; Wang, J.J.; Guan, R.; Du, L.; Gao, J.; Fu, X.L. Strategies to target glucose metabolism in TUMOR microenvironment on cancer by flavonoids. Nutr. Cancer, 2017, 69, 534-554.
[50]
Lin, S.T.; Tu, S.H.; Yang, P.S.; Hsu, S.P.; Lee, W.H.; Ho, C.T.; Wu, C.H.; Lai, Y.H.; Chen, M.Y.; Chen, L.C. Apple polyphenol phloretin inhibits colorectal cancer cell growth via inhibition of the type 2 glucose transporter and activation of p53-mediated signaling. J. Agric. Food Chem., 2016, 64, 6826-6837.
[51]
Wu, C.H.; Ho, Y.S.; Tsai, C.Y.; Wang, Y.J.; Tseng, H.; Wei, P.L.; Lee, C.H.; Liu, R.S.; Lin, S.Y. In vitro and in vivo study of Phloretin‐induced apoptosis in human liver cancer cells involving inhibition of type II glucose transporter. Int. J. Cancer, 2009, 124, 2210-2219.
[52]
Sampath, C.; Rashid, M.R.; Sang, S.; Ahmedna, M. Specific bioactive compounds in ginger and apple alleviate hyperglycemia in mice with high fat diet-induced obesity via Nrf2 mediated pathway. Food Chem., 2017, 226, 79-88.
[53]
Shen, X.; Zhou, N.; Mi, L.; Hu, Z.; Wang, L.; Liu, X.; Zhang, S. Phloretin exerts hypoglycemic effect in streptozotocin-induced diabetic rats and improves insulin resistance in vitro. Drug Des. Devel. Ther., 2017, 11, 313-324.
[54]
Alsanea, S.; Gao, M.; Liu, D. Phloretin prevents high-fat diet-induced obesity and improves metabolic homeostasis. AAPS J., 2017, 19, 797-805.
[55]
Natanzi, E.; Reza, A.; Mahmoudian, S.; Minaeie, B.; Sabzevari, O. Hepatoprotective activity of phloretin and hydroxychalcones against acetaminophen induced hepatotoxicity in mice. Iran. J. Pharm. Res., 2011, 7, 89-97.
[56]
Zuo, A.R.; Yu, Y.Y.; Shu, Q.L.; Zheng, L.X.; Wang, X.M.; Peng, S.H.; Xie, Y.F.; Cao, S.W. Hepatoprotective effects and antioxidant, antityrosinase activities of phloretin and phloretin isonicotinyl hydrazone. J. Chin. Med. Assoc., 2014, 77, 290-301.
[57]
Ren, D.; Liu, Y.; Zhao, Y.; Yang, X. Hepatotoxicity and endothelial dysfunction induced by high choline diet and the protective effects of phloretin in mice. Food Chem. Toxicol., 2016, 94, 203-212.
[58]
An, R.B.; Park, E.J.; Jeong, G.S.; Sohn, D.H.; Kim, Y.C. Cytoprotective constituent of Hoveniae Lignum on both Hep G2 cells and rat primary hepatocytes. Arch. Pharm. Res., 2007, 30, 674-677.
[59]
Zhang, S.; Morris, M.E. Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport. J. Pharmacol. Exp. Ther., 2003, 304, 1258-1267.
[60]
Shuai-Cheng, W.; Ben-Dong, F.; Xiu-Ling, C.; Jian-Qing, S.; Yun-Xing, F.; Zhen-Qiang, C.; Dao-Xiu, X.; Zong-Mei, W. Subinhibitory concentrations of phloretin repress the virulence of Salmonella typhimurium and protect against Salmonella typhimurium infection. Antonie van Leeuwenhoek, 2016, 109, 1503-1512.
[61]
Jeon, D.; Jeong, M.C.; Jnawali, H.N.; Kwak, C.; Ryoo, S.; Jung, I.D.; Kim, Y. Phloretin exerts anti-tuberculosis activity and suppresses lung inflammation. Molecules, 2017, 22, E183.
[62]
Wang, J.; Liu, B.; Teng, Z.; Zhou, X.; Wang, X.; Zhang, B.; Lu, G.; Niu, X.; Yang, Y.; Deng, X. Phloretin attenuates listeria monocytogenes virulence both in vitro and in vivo by simultaneously targeting listeriolysin O and sortase A. Front. Cell. Infect. Microbiol., 2017, 7, 9.
[http://dx.doi.org/10.3389/fcimb.2017.00009]
[63]
Lu, X.Y.; Zeng, Y.Y. k Ye, Y.X.; Zhou, Y.Y.; Mu, J.J.; Zhao, X.H. Anti-Inflammatory and immunosuppressive effect of phloretin. Acta Pharm. Sin, 2009, 44, 480-485.
[64]
Ullen, A.; Fauler, G.; Bernhart, E.; Nusshold, C.; Reicher, H.; Leis, H.J.; Malle, E.; Sattler, W. Phloretin ameliorates 2-chlorohexadecanal-mediated brain microvascular endothelial cell dysfunction in vitro. Free Radic. Biol. Med., 2012, 53, 1770-1781.
[65]
Barreca, D.; Curro, M.; Bellocco, E.; Ficarra, S.; Lagana, G.; Tellone, E. Laura, Giunta M, Visalli, G.; Caccamo, D.; Galtieri, A.; Ientile, R. Neuroprotective effects of phloretin and its glycosylated derivative on rotenone-induced toxicity in human SH-SY5Y neuronal-like cells. Biofactors, 2017, 43, 549-557.
[66]
Oresajo, C.; Stephens, T.; Hino, P.D.; Law, R.M.; Yatskayer, M.; Foltis, P.; Pillai, S.; Pinnell, S.R. Protective effects of a topical antioxidant mixture containing vitamin C, ferulic acid, and phloretin against ultraviolet‐induced photodamage in human skin. J. Cosmet. Dermatol., 2008, 7, 290-297.
[67]
Shin, S.; Kum, H.; Ryu, D.; Kim, M.; Jung, E.; Park, D. Protective effects of a new Phloretin derivative against UVB-induced damage in skin cell model and human volunteers. Int. J. Mol. Sci., 2014, 5, 18919-18940.
[68]
Crespy, V.; Aprikian, O.; Morand, C.; Besson, C.; Manach, C.; Demigne, C.; Remesy, C. Bioavailability of phloretin and phloridzin in rats. J. Nutr., 2001, 131, 3227-3230.
[69]
Remsberg, C.M.; Yanez, J.A.; Vega-Villa, K.R.; Davies, N.M.; Miranda, N.D.; Andrews, P.K.; Davies, N.M. HPLC-UV analysis of phloretin in biological fluids and application to pre-clinical pharmacokinetic studies. J. Bioremediat. Biodegrad., 2010, 1, 101.


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Article Details

VOLUME: 19
ISSUE: 13
Year: 2019
Published on: 20 August, 2019
Page: [1060 - 1067]
Pages: 8
DOI: 10.2174/1389557519666190311154425
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