Display options
Share it on

J Food Biochem. 2021 Nov 07;e13999. doi: 10.1111/jfbc.13999. Epub 2021 Nov 07.

Effectiveness of a new rutin Cu(II) complex in the prevention of lipid peroxidation and hepatotoxicity in hypercholesterolemic rats.

Journal of food biochemistry

Daniel A F de Oliveira, Susana N Diniz, Regina M S Pereira, Ivair D Gonçalves, André L Rennó, Renata Gorjão, Eduardo G Vieira, Ana M da C Ferreira, Cristina E Okuyama

Affiliations

  1. Universidade Anhanguera de São Paulo (UNIAN), São Paulo, Brazil.
  2. Faculty of Pharmacy, Centro Universitário de Jaguariúna (UNIFAJ), Jaguariúna, Brazil.
  3. Faculty of Medicine, Faculdade São Leopoldo Mandic (SLM), Campinas, Brazil.
  4. Program of Interdisciplinary Postgraduate in Health Sciences, Universidade Cruzeiro do Sul (UNICSUL), São Paulo, Brazil.
  5. Institute of Chemistry, Universidade de São Paulo (USP), São Paulo, Brazil.

PMID: 34747031 DOI: 10.1111/jfbc.13999

Abstract

A new rutin copper(II) complex (R-Cu2) was prepared and characterized by spectroscopic methods and elemental analysis. The effects of rutin and R-Cu2 were evaluated on the prevention of hypercholesterolemia in animals feed with high-cholesterol diet (HCD) for 8 weeks. The animals (n = 5) were neither fed with HCD nor treated (control group), or were treated with vehicle, 10 mg/kg simvastatin, rutin (16 and 160 μmol/kg), and R-Cu2 (16 and 160 μmol/kg) administered orally. Total cholesterol (TC) levels were significantly increased (p < .01) in all HCD groups. In rutin and R-Cu2 groups, it was observed a discrete, but not significant, TC and LDL-induced increase inhibition compared with vehicle-treated group. R-Cu2 treatment significantly decreased (p < .05) plasma triglycerides compared with the vehicle-treated group. All groups receiving treatments maintained the malondialdehyde at normal levels. Serum NO levels were reduced in animals treated with rutin and R-Cu2 compared with the vehicle-treated group. In addition, the results also showed that the groups treated with rutin and R-Cu2 reduced significantly (p < .01), the number of neutrophils and prevented histological changes in all evaluated liver zones. R-Cu2 group maintained the ALT, AST, and ALP enzymes at normal levels. Thus, the effects of R-Cu2 in modulating inflammation and protecting liver damage were confirmed. PRACTICAL APPLICATIONS: Rutin, a plant-derived flavonoid, is one of phenolic compounds well known as a nutraceutical due to its antioxidant and anti-inflammatory properties. Findings of this study demonstrate the effects of both rutin and R-Cu2 in modulating inflammation and protecting liver damage in hypercholesterolemic rats. However, some effects analyzed became more evident in R-Cu2. Thereby, it was shown that the synthesis of a new flavonoid compound (R-Cu2) could be applied as a nutraceutical benefit option to prevent hypercholesterolemia condition.

© 2021 Wiley Periodicals LLC.

Keywords: copper; flavonoid; hypercholesterolemia; lipid peroxidation; rutin

References

  1. Abdelhalim, M. A. K., Moussa, S. A. A., & Qaid, H. A. Y. (2018). The protective role of quercetin and arginine on gold nanoparticles induced hepatotoxicity in rats. International Journal of Nanomedicine, 13, 2821-2825. https://doi.org/10.2147/IJN.S160995 - PubMed
  2. Al-Rejaie, S. S., Aleisa, A. M., Sayed-Ahmed, M. M., Al-Shabanah, O. A., Abuohashish, H. M., Ahmed, M. M., Al-Hosaini, K. A., & Hafez, M. M. (2013). Protective effect of rutin on the antioxidant genes expression in hypercholestrolemic male Westar rat. BMC Complementary and Alternative Medicine, 13, 136. https://doi.org/10.1186/1472-6882-13-136 - PubMed
  3. AlSharari, S. D., Al-Rejaie, S. S., Abuohashish, H. M., Ahmed, M. M., & Hafez, M. M. (2016). Rutin attenuates hepatotoxicity in high-cholesterol-diet-fed rats. Oxidative Medicine and Cellular Longevity, 2016, 5436745. https://doi.org/10.1155/2016/5436745 - PubMed
  4. Andersson, C., & Vasan, R. S. (2018). Epidemiology of cardiovascular disease in young individuals. Nature Reviews Cardiology, 15, 230-240. https://doi.org/10.1038/nrcardio.2017.154 - PubMed
  5. Atoui, A. K., Mansouri, A., Boskou, G., & Kefalas, P. (2005). Tea and herbal infusions: Their antioxidant activity and phenolic profile. Food Chemistry, 89, 27-36. https://doi.org/10.1016/j.foodchem.2004.01.075 - PubMed
  6. Bernatoniene, J., & Kopustinskiene, D. M. (2018). The role of catechins in cellular responses to oxidative stress. Molecules, 23(4), 965. https://doi.org/10.3390/molecules23040965 - PubMed
  7. Bukhari, S. B., Memon, S., Tahir, M. M., & Bhanger, M. I. (2009). Synthesis, characterization and investigation of antioxidant activity of cobalt-quercetin complex. Journal of Molecular Structure, 892, 39-46. https://doi.org/10.1016/j.molstruc.2008.04.050 - PubMed
  8. Castillo, R. L., Herrera, E. A., Gonzalez-Candia, A., Reyes-Farias, M., de la Jara, N., Peña, J. P., & Carrasco-Pozo, C. (2018). Quercetin prevents diastolic dysfunction induced by a high- cholesterol diet: Role of oxidative stress and bioenergetics in hyperglycemic rats. Oxidative Medicine and Cellular Longevity, 2018, 7239123. https://doi.org/10.1155/2018/7239123 - PubMed
  9. Castro Cabezas, M., Burggraaf, B., & Klop, B. (2018). Dyslipidemias in clinical practice. Clinica Chimica Acta, 487, 117-125. https://doi.org/10.1016/j.cca.2018.09.010 - PubMed
  10. Cencic, A., & Chingwaru, W. (2010). Cencic, A., Chingwaru, W. (2010). The role of functional foods nutraceuticals and food supplements in intestinal health. Nutrients, 2, 611-625. https://doi.org/10.3390/nu2060611.. Nutrients, 2, 611-625. https://doi.org/10.3390/nu2060611. - PubMed
  11. Chanet, A., Milenkovic, D., Deval, C., Potierb, M., Constansc, J., Mazur, A., Bennetau-Pelisserob, C., Morand, C., & Bérardc, A. M. (2012). Naringin, the major grapefruit flavonoid, specifically affects atherosclerosis development in diet-induced hypercholesterolemia in mice. Journal of Nutritional Biochemistry, 23, 469-477. https://doi.org/10.1016/j.jnutbio.2011.02.001 - PubMed
  12. Chitturi, S., & George, J. (2002). Hepatotoxicity of commonly used drugs: Nonsteroidal anti-inflammatory drugs, antihypertensives, antidiabetic agents, anticonvulsants, lipid-lowering agents, psychotropic drugs. Seminars in Liver Disease, 22, 169-183. https://doi.org/10.1055/s-2002-30102 - PubMed
  13. Chtourou, Y., Slima, A. B., Makni, M., Gdoura, R., & Fetoui, H. (2015). Naringenin protects cardiac hypercholesterolemia-induced oxidative stress and subsequent necroptosis in rats. Pharmacological Reports, 67, 1090-1097. https://doi.org/10.1016/j.pharep.2015.04.002 - PubMed
  14. Clark, J. L., Zahradka, P., & Taylor, C. G. (2015). Efficacy of flavonoids in the management of high blood pressure. Nutrition Reviews, 73, 799-822. https://doi.org/10.1093/nutrit/nuv048 - PubMed
  15. Dowling, S., Regan, F., & Hughes, H. (2010). The characterisation of structural and antioxidant properties of isoflavone metal chelates. Journal of Inorganic Biochemistry, 104, 1091-1098. https://doi.org/10.1016/j.jinorgbio.2010.06.007 - PubMed
  16. Drechsler, M., Megens, R. T., van Zandvoort, M., Weber, C., & Soehnlein, O. (2010). Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation, 122, 1837-1845. https://doi.org/10.1161/CIRCULATIONAHA.110.961714 - PubMed
  17. Green, L. C., Wagner, D. A., Glogowski, K., Skipper, P. L., Wishnok, J. S., & Tannenbaum, S. R. (1982). Analysis of nitrate, nitrite and [15N]nitrate in biological fluids. Analytical Biochemistry, 126, 131-138. https://doi.org/10.1016/0003-2697(82)90118-X - PubMed
  18. Hazen, S. L. (2010). Neutrophils, hypercholesterolemia and atherogenesis. Circulation, 122, 1786-1788. https://doi.org/10.1161/CIRCULATIONAHA.110.984062 - PubMed
  19. Hosseinzadeh, H., & Nassiri-Asl, M. (2014). Review of the protective effects of rutin on the metabolic function as an important dietary flavonoid. Journal of Endocrinological Investigation, 37, 783-788. https://doi.org/10.1007/s40618-014-0096-3 - PubMed
  20. Ikeda, N. E., Novak, E. M., Maria, D. A., Velosa, A. S., & Pereira, R. M. (2015). Synthesis, characterization and biological evaluation of Rutin-zinc(II) flavonoid-metal complex. Chemico-Biological Interactions, 239, 184-191. https://doi.org/10.1016/j.cbi.2015.06.011 - PubMed
  21. Justino, A. B., Miranda, N. C., Franco, R. R., Martins, M. M., Silva, N. M. D., & Espindola, F. S. (2018). Annona muricata Linn. Leaf as a source of antioxidant compounds with in vitro antidiabetic and inhibitory potential against α-amylase, α-glucosidase, lipase, non-enzymatic glycation and lipid peroxidation. Biomedicine & Pharmacotherapy, 100, 83-92. https://doi.org/10.1016/j.biopha.2018.01.172 - PubMed
  22. Juźwiak, S., Wójcicki, J., Mokrzycki, K., Marchlewicz, M., Białecka, M., Wenda-Rózewicka, L., Gawrońska-Szklarz, B., & Droździk, M. (2005). Effect of quercetin on experimental hyperlipidemia and atherosclerosis in rabbits. Pharmacological Reports, 57, 604-609. - PubMed
  23. Kamada, C., Silva, E. L., Ohnishi-Kameyama, M., Moon, J. H., & Terao, J. (2005). Attenuation of lipid peroxidation and hyperlipidemia by quercetin glucoside in the aorta of high cholesterol-fed rabbit. Free Radical Research, 39, 185-194. https://doi.org/10.1080/10715760400019638 - PubMed
  24. Kanashiro, A., Andrade, D. C. O., Kabeya, L. M., Turato, W. M., Faccioli, L. H., Uyemura, S. A., & Lucisano-Valim, Y. M. (2009). Modulatory effects of rutin on biochemical and hematological parameters in hypercholesterolemic Golden Syrian hamsters. An Anais Da Academia Brasileira De Ciências, 81, 67-72. https://doi.org/10.1590/S0001-37652009000100009 - PubMed
  25. Khosravi, M., Hosseini-Fard, R., & Najafi, M. (2018). Circulating low density lipoprotein (LDL). Hormone Molecular Biology and Clinical Investigation, 35(2), 24. https://doi.org/10.1515/hmbci-2018-0024 - PubMed
  26. Kostyuk, V. A., Potapovich, A. I., Kostyuk, T. V., & Cherian, M. G. (2007). Metal complexes of dietary flavonoids: Evaluation of radical scavenger properties and protective activity against oxidative stress in vivo. Cellular and Molecular Biology, 53, 62-69. - PubMed
  27. Kreft, I., Fabjan, N., & Yasumoto, K. (2006). Rutin content in buckwheat (Fagopyrum esculentum Moench) food materials and products. Food Chemistry, 98, 508-512. https://doi.org/10.1016/j.foodchem.2005.05.081 - PubMed
  28. Kuipers, E. N., van Dam, A. D., Held, N. M., Mol, I. M., Houtkooper, R. H., Rensen, P. C. N., & Boon, M. R. (2018). Quercetin lowers plasma triglycerides accompanied by white adipose tissue browning in diet-induced obese mice. International Journal of Molecular Sciences, 19(6), 1786. https://doi.org/10.3390/ijms19061786 - PubMed
  29. Kumar, S., & Pandey, A. K. (2013). Chemistry and biological activities of flavonoids: An overview. Scientific World Journal, 2013, 1-16. https://doi.org/10.1155/2013/162750 - PubMed
  30. Lima, L. P. R., Oliveira, T. T., Nagem, T. J., Pinto, A. S., Lima, E. Q., & Silva, J. F. (2003). Toxidade aguda de rutina e bixina de Bixa orellana. Acta Farmacéutica Bonaerense, 22(1), 21-26. - PubMed
  31. Liu, Q., Pan, R., Ding, L., Zhang, F., Hu, L., Ding, B., Zhu, L., Xia, Y., & Dou, X. (2017). Rutin exhibits hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease by reducing hepatic lipid levels and mitigating lipid-induced oxidative injuries. International Immunopharmacology, 49, 132-141. https://doi.org/10.1016/j.intimp.2017.05.026 - PubMed
  32. Miyashiro, C. A. H. V., Diniz, S. N., Oliveira, D. A. F., Gonçalves, I. D., Pereira, R. M. S., Silva, R. G., Paulino, N., & Okuyama, C. E. (2014). The potentiation of anti-inflammatory effect and iNOS and COX-2 gene expression inhibition by rut in when complexed with copper. Journal of Advances in Medicine and Medical Research, 25, 4289-4309. https://doi.org/10.9734/BJMMR/2014/10228 - PubMed
  33. Mozaffarian, D., & Wu, J. H. Y. (2018). Flavonoids, dairy foods, and cardiovascular and metabolic health: a Review of emerging biologic pathways. Circulation Research, 19, 369-384. https://doi.org/10.1161/CIRCRESAHA.117.309008 - PubMed
  34. Münzel, T., Heitzer, T., & Harrison, D. G. (1997). The physiology and pathophysiology of the nitric oxide/superoxide system. Herz, 22, 158-172. https://doi.org/10.1007/BF03044353 - PubMed
  35. Nicastro, H., Da Luz, C. R., Chaves, D. F., Das Neves, W., Valente, K. S., & Lancha, A. H. Jr (2012). Leucine supplementation combined with resistance exercise improves the plasma lipid profile of dexamethasone-treated rats. Lipids in Health and Disease, 11, 7. https://doi.org/10.1186/1476-511X-11-7 - PubMed
  36. Novak, E. M., Pereira, R. M., Ikeda, N. E. A., Bydlowski, S. P., Velosa, A. S. V., Paulino, N., & Okuyama, C. E. (2021). Method of production of zinc coordination complex rutin, rutin complex zinc, pharmaceutical and/or cosmetic compositions and their uses. INPI patent. n.1100782-6, 16/03/2021. - PubMed
  37. Olaleye, M. T., Crown, O. O., Akinmoladun, A. C., & Akindahunsi, A. A. (2014). Rutin and quercetin show greater efficacy than nifedipine in ameliorating hemodynamic, redox, and metabolite imbalances in sodium chloride-induced hypertensive rats. Human and Experimental Toxicology, 33, 602-608. https://doi.org/10.1177/0960327113504790 - PubMed
  38. Orhan, I. E., Nabavi, S. F., Daglia, M., Tenore, G. C., Mansouri, K., & Nabavi, S. M. (2015). Naringenin and atherosclerosis: A review of literature. Current Pharmaceutical Biotechnology, 16, 245-251. - PubMed
  39. Pant, S., Deshmukh, A., Gurumurthy, G. S., Pothineni, N. V., Watts, T. E., Romeo, F., & Mehta, J. L. (2014). Inflammation and atherosclerosis - revisited. Journal of Cardiovascular Pharmacology and Therapeutics, 19, 170-178. https://doi.org/10.1177/1074248413504994 - PubMed
  40. Peixoto, J. C., Neves, B. J., Vasconcelos, F. G., Napolitano, H. B., Barbalho, M. G. D. S., Silva, S. D. E., & Rosseto, L. P. (2019). Flavonoids from Brazilian Cerrado: Biosynthesis, chemical and biological profile. Molecules, 24, 2891. https://doi.org/10.3390/molecules24162891 - PubMed
  41. Peng, H., Zhuang, Y., Chen, Y., Rizzo, A. N., & Chen, W. (2015). The characteristics and regulatory mechanisms of superoxide generation from eNOS reductase domain. PLoS One, 10, e0140365. https://doi.org/10.1371/journal.pone.0140365 - PubMed
  42. Pereira, R. M., Andrades, N. E., Paulino, N., Sawaya, A. C., Eberlin, M. N., Marcucci, M. C., Favero, G. M., Novak, E. M., & Bydlowski, S. P. (2007). Synthesis and characterization of a metal complex containing naringin and Cu, and its antioxidant, antimicrobial, antiinflammatory and tumor cell cytotoxicity. Molecules, 12, 1352-1366. https://doi.org/10.3390/12071352 - PubMed
  43. Porez, G., Prawitt, J., Gross, B., & Staels, B. (2012). Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease. Journal of Lipid Research, 53, 1723-1737. https://doi.org/10.1194/jlr.R024794 - PubMed
  44. Raza, A., Bano, S., Xu, X., Zhang, R. X., Khalid, H., Iqbal, F. M., Xia, C., Tang, J., & Ouyang, Z. (2017). Rutin-nickel complex: Synthesis, characterization, antioxidant, DNA binding, and DNA cleavage activities. Biological Trace Element Research, 178, 160-169. https://doi.org/10.1007/s12011-016-0909-7 - PubMed
  45. Roy, S., Banerjee, S., & Chakraborty, T. (2018). Vanadium quercetin complex attenuates mammary cancer by regulating the P53, Akt/mTOR pathway and downregulates cellular proliferation correlated with increased apoptotic events. BioMetals, 31, 647-671. https://doi.org/10.1007/s10534-018-0117-3 - PubMed
  46. Selvaraj, S., Krishnaswamy, S., Devashya, V., Sethuraman, S., & Krishnan, U. M. (2013). Flavonoid-metal ion complexes: A novel class of therapeutic agents. Medicinal Research Reviews, 34(4), 677-702. https://doi.org/10.1002/med.21301 - PubMed
  47. Serra, J. A., Dominguez, R. O., De Lustig, E. S., Guareschi, E. M., Famulari, A. L., Bartolomé, E. L., & Marschoff, E. R. (2001). Parkinson’s disease is associated with oxidative stress: Comparison of peripheral antioxidant profiles in living Parkinson’s, Alzheimer’s and vascular dementia patients. Journal of Neural Transmission, 108, 1135-1148. https://doi.org/10.1007/s007020170003 - PubMed
  48. Shattat, G. F. (2014). A review article on hyperlipidemia: Types, treatments and new drug targets. Biomedical and Pharmacology Journal, 7, 399-409. https://doi.org/10.13005/bpj/504 - PubMed
  49. Subramanian, S., Turner, M. S., Ding, Y., Goodspeed, L., Wang, S., Buckner, J. H., O'Brien, K., Getz, G. S., Reardon, C. A., & Chait, A. (2013). Increased levels of invariant natural killer T lymphocytes worsen metabolic abnormalities and atherosclerosis in obese mice. Journal of Lipid Research, 54, 2831-2841. https://doi.org/10.1194/jlr.M041020 - PubMed
  50. Szerzsunowicz, I., & Klobukowski, J. (2020). Characteristics of potential protein nutraceuticals of plant origin with antioxidant activity. Molecules, 25(7), 1621. https://doi.org/10.3390/molecules25071621 - PubMed
  51. Szparaga, A., Kocira, S., Kocira, A., Czerwińska, E., Świeca, M., Lorencowicz, E., Kornas, R., Koszel, M., & Oniszczuk, T. (2018). Modification of growth, yield, and the nutraceutical and antioxidative potential of soybean through the use of synthetic biostimulants. Frontiers in Plant Science, 9, 1401. https://doi.org/10.3389/fpls.2018.01401 - PubMed
  52. Takamura, T. A., Tsuchiya, T., Oda, M., Watanabe, M., Saito, R., Sato-Ishida, R., Akao, H., Kawai, Y., Kitayama, M., & Kajinami, K. (2017). Circulating malondialdehyde-modified low-density lipoprotein (MDA-LDL) as a novel predictor of clinical outcome after endovascular therapy in patients with peripheral artery disease (PAD). Atherosclerosis, 263, 192-197. https://doi.org/10.1016/j.atherosclerosis.2017.06.029 - PubMed
  53. Tamura, T., Mitsumori, K., Muto, S., Kasahara, H., Kobayashi, S., Okuhara, Y., Hayashi, M., Nagasawa, T., Onozato, T., & Kuroda, J. (2010). Fifty-two week chronic toxicity of enzymatically decomposed rutin in Wistar rats. Food and Chemical Toxicology, 48, 2312-2318. https://doi.org/10.1016/j.fct.2010.05.065 - PubMed
  54. Tan, M., Zhu, J., Pan, Y., Chen, Z., Liang, H., Liu, H., & Wang, H. (2009). Synthesis, cytotoxic activity, and DNA binding properties of copper (II) complexes with hesperetin, naringenin, and apigenin. Bioinorganic Chemistry and Applications, 2009, 1-9. https://doi.org/10.1155/2009/347872 - PubMed
  55. Vaghasiya, J., Rathod, S., Bhalodia, Y., Manek, R., Malaviya, S., & Jivani, N. (2009). Protective effect of polyherbal formulation on simvastatin hepatotoxicity in rats. Journal of Young Pharmacists, 1, 57. https://doi.org/10.4103/0975-1483.51883 - PubMed
  56. Wang, L., Wang, B. O., Li, H., Lu, H., Qiu, F., Xiong, L., Xu, Y., Wang, G., Liu, X., Wu, H., & Jing, H. (2012). Quercetin, a flavonoid with anti-inflammatory activity, suppresses the development of abdominal aortic aneurysms in mice. European Journal of Pharmacology, 690, 133-141. https://doi.org/10.1016/j.ejphar.2012.06.018 - PubMed
  57. Wong, B. W., Meredith, A., Lin, D., & McManus, B. M. (2012). The biological role of inflammation in atherosclerosis. Canadian Journal of Cardiology, 28, 631-641. https://doi.org/10.1016/j.cjca.2012.06.023 - PubMed
  58. Wu, C. C., Wang, S. H., Kuan, I. I., Tseng, W. K., Chen, M. F., Wu, J. C., & Chen, Y. L. (2009). OxLDL upregulates caveolin-1 expression in macrophages: Role for caveolin-1 in the adhesion of oxLDL-treated macrophages to endothelium. Journal of Cellular Biochemistry, 107, 460-472. https://doi.org/10.1002/jcb.22144 - PubMed
  59. Yokoyama, A., Yokoyama, A., Sakakibara, H., Yokoyama, A., Sakakibara, H., Crozier, A., Kawai, Y., Matsui, A., Terao, J., Kumazawa, S., & Shimoi, K. (2009). Quercetin metabolites and protection against peroxynitrite-induced oxidative hepatic injury in rats. Free Radical Research, 43, 913-921. https://doi.org/10.1080/10715760903137010 - PubMed
  60. Zand, T., Hoffman, A. H., Savilonis, B. J., Underwood, J. M., Nunnari, J. J., Majno, G., & Joris, I. (1999). Lipid deposition in rat aortas with intraluminal hemispherical plug stenosis: A morphological and biophysical study. American Journal of Pathology, 155, 85-92. https://doi.org/10.1016/S0002-9440(10)65103-6 - PubMed
  61. Zimmermann, M. (1983). Ethical guidelines for investigations of experimental pain in conscious animals. Pain, 16, 109-110. https://doi.org/10.1016/0304-3959(83)90201-4 - PubMed

Publication Types

Grant support