Abstract
Cyclophosphamide (CYP) is a common anticancer drug used in the treatment of various malignancies. Naringin (NG) is a natural bioflavonoid that have been reported to have many medicinal and pharmacological properties. Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carbonic anhydrase (CA), α-glycosidase (α-Gly), and aldose reductase (AR) enzymes are the essential biological molecules needed for metabolic processes in all living cells. In the present study, the aim was to investigate the effect of NG against CYP-induced liver, brain, kidney, heart, and testis toxicities on some metabolic enzyme activities such as AChE, BChE, CA, α-Gly, and AR. Thirty-five male Wistar rats were randomly divided into five groups with each group consisting of seven rats. The rats were subjected to oral treatment of NG (50 and 100 mg/kg body weight) for 7 days before administering a single dose of CYP (200 mg/kg body weight, i.p) on the seventh day. Treatment with NG in all tissues regulated these enzyme activities in CYP-induced rats. The results of this study showed that NG regulates abnormal increases and decreases in CYP-induced metabolic enzyme activities in all tissues.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-019-05915-3/MediaObjects/11356_2019_5915_Fig1_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-019-05915-3/MediaObjects/11356_2019_5915_Fig2_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-019-05915-3/MediaObjects/11356_2019_5915_Fig3_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-019-05915-3/MediaObjects/11356_2019_5915_Fig4_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-019-05915-3/MediaObjects/11356_2019_5915_Fig5_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-019-05915-3/MediaObjects/11356_2019_5915_Fig6_HTML.png)
Similar content being viewed by others
References
Ak T, Gülçin İ (2008) Antioxidant and radical scavenging properties of curcumin. Chem Biol Interact 174:27–37
Aksu K, Özgeriş B, Taslimi P, Naderi A, Gülçin İ, Göksu S (2016) Antioxidant activity, acetylcholinesterase, and carbonic anhydrase inhibitory properties of novel ureas derived from phenethylamines. Arch Pharm 349:944–954
Ashiq U, Jamal RA, Saleem M, Mahroof-Tahir M (2017) Alpha-glucosidase and carbonic anhydrase inhibition studies of Pd (II)-hydrazide complexes. Arab J Chem 10:488–499
Aslan HE, Beydemir Ş (2017) Phenolic compounds: the inhibition effect on polyol pathway enzymes. Chem Biol Interact 266:47–55
Barreca D, Bellocco E, Laganà G, Ginestra G, Bisignano C (2014) Biochemical and antimicrobial activity of phloretin and its glycosilated derivatives present in apple and kumquat. Food Chem 160:292–297
Bayrak Ç, Taslimi P, Gülçin İ, Menzek A (2017) The first synthesis of 4-phenylbutenone derivative bromophenols including natural products and their inhibition profiles for carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase enzymes. Bioorg Chem 72:359–366
Benzer F, Kandemir FM, Kucukler S, Comaklı S, Caglayan C (2018) Chemoprotective effects of curcumin on doxorubicin-induced nephrotoxicity in wistar rats: by modulating inflammatory cytokines, apoptosis, oxidative stress and oxidative DNA damage. Arch Physiol Biochem 1–10
Caglayan C, Gulcin İ (2018) The toxicological effects of some avermectins on goat liver carbonic anhydrase enzyme. J Biochem Mol Toxicol 32:e22010
Caglayan C, Demir Y, Kucukler S, Taslimi P, Kandemir FM, Gulçin İ (2018a) The effects of hesperidin on sodium arsenite-induced different organ toxicity in rats on metabolic enzymes as antidiabetic and anticholinergics potentials: a biochemical approach. J Food Biochem:e12720
Caglayan C, Kandemir FM, Yıldırım S, Kucukler S, Kılınc MA, Saglam YS (2018b) Zingerone ameliorates cisplatin-induced ovarian and uterine toxicity via suppression of sex hormone imbalances, oxidative stress, inflammation and apoptosis in female wistar rats. Biomed Pharmacother 102:517–530
Caglayan C, Temel Y, Kandemir FM, Yildirim S, Kucukler S (2018c): Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage. Environ Sci Pollut Res, 1–17
Cao H, Chen X, Jassbi AR, Xiao J (2015) Microbial biotransformation of bioactive flavonoids. Biotechnol Adv 33:214–223
Cerelli MJ, Curtis DL, Dunn JP, Nelson PH, Peak TM, Waterbury LD (1986) Antiinflammatory and aldose reductase inhibitory activity of some tricyclic arylacetic acids. J Med Chem 29:2347–2351
Chtourou Y, Aouey B, Kebieche M, Fetoui H (2015) Protective role of naringin against cisplatin induced oxidative stress, inflammatory response and apoptosis in rat striatum via suppressing ROS-mediated NF-κB and P53 signaling pathways. Chem Biol Interact 239:76–86
Demir Y, Işık M, Gülçin İ, Beydemir Ş (2017) Phenolic compounds inhibit the aldose reductase enzyme from the sheep kidney. J Biochem Mol Toxicol 31:e21936
Deng J, Zhong Y-F, Wu Y-P, Luo Z, Sun Y-M, Wang G-E, Kurihara H, Li Y-F, He R-R (2018) Carnosine attenuates cyclophosphamide-induced bone marrow suppression by reducing oxidative DNA damage. Redox Biol 14:1–6
Eldutar E, Kandemir FM, Kucukler S, Caglayan C (2017) Restorative effects of Chrysin pretreatment on oxidant–antioxidant status, inflammatory cytokine production, and apoptotic and autophagic markers in acute paracetamol-induced hepatotoxicity in rats: an experimental and biochemical study. J Biochem Mol Toxicol 31:e21960
Fouad AA, Qutub HO, Al-Melhim WN (2016) Punicalagin alleviates hepatotoxicity in rats challenged with cyclophosphamide. Environ Toxicol Pharmacol 45:158–162
Göksu S, Naderi A, Akbaba Y, Kalın P, Akıncıoğlu A, Gülçin İ, Durdagi S, Salmas RE (2014) Carbonic anhydrase inhibitory properties of novel benzylsulfamides using molecular modeling and experimental studies. Bioorg Chem 56:75–82
Gülçin İ, Scozzafava A, Supuran CT, Koksal Z, Turkan F, Çetinkaya S, Bingöl Z, Huyut Z, Alwasel SH (2016) Rosmarinic acid inhibits some metabolic enzymes including glutathione S-transferase, lactoperoxidase, acetylcholinesterase, butyrylcholinesterase and carbonic anhydrase isoenzymes. J Enzyme Inhib Med Chem 31:1698–1702
Gulçin İ, Abbasova M, Taslimi P, Huyut Z, Safarova L, Sujayev A, Farzaliyev V, Beydemir Ş, Alwasel SH, Supuran CT (2017) Synthesis and biological evaluation of aminomethyl and alkoxymethyl derivatives as carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase inhibitors. J Enzyme Inhib Med Chem 32:1174–1182
Guo Z, Niu X, Xiao T, Lu J, Li W, Zhao Y (2015) Chemical profile and inhibition of α-glycosidase and protein tyrosine phosphatase 1B (PTP1B) activities by flavonoids from licorice (Glycyrrhiza uralensis Fisch). J Funct Foods 14:324–336
Habibi E, Shokrzadeh M, Chabra A, Naghshvar F, Keshavarz-Maleki R, Ahmadi A (2015) Protective effects of Origanum vulgare ethanol extract against cyclophosphamide-induced liver toxicity in mice. Pharm Biol 53:10–15
Jagetia G, Lalrinengi C (2017) Treatment of mice with naringin alleviates the doxorubicin-induced oxidative stress in the liver of Swiss albino mice. MOJ Anat Physiol 4:00130
Jagetia GC, Reddy TK (2014) The grape fruit flavonone naringin protects mice against doxorubicin-induced cardiotoxicity. J Mol Biochem:3
Jalali AS, Hasanzadeh S, Malekinejad H (2012) Crataegus monogyna aqueous extract ameliorates cyclophosphamide-induced toxicity in rat testis: stereological evidences. Acta Med Iran 50:1–8
Kandemir F, Küçükler S, Çağlayan C (2017a) Beneficial effects of silymarin and naringin against methotrexate-induced hepatotoxicity in rats. Atatürk Üniversitesi Veteriner Bilimleri Dergisi 12:167–177
Kandemir FM, Kucukler S, Caglayan C, Gur C, Batil AA, Gülçin İ (2017b) Therapeutic effects of silymarin and naringin on methotrexate-induced nephrotoxicity in rats: biochemical evaluation of anti-inflammatory, antiapoptotic, and antiautophagic properties. J Food Biochem 41:e12398
Kandemir FM, Ozkaraca M, Küçükler S, Caglayan C, Hanedan B (2018a) Preventive effects of hesperidin on diabetic nephropathy induced by streptozotocin via modulating TGF-β1 and oxidative DNA damage. Toxin Rev 37:287–293
Kandemir FM, Yildirim S, Kucukler S, Caglayan C, Mahamadu A, Dortbudak MB (2018b) Therapeutic efficacy of zingerone against vancomycin-induced oxidative stress, inflammation, apoptosis and aquaporin 1 permeability in rat kidney. Biomed Pharmacother 105:981–991
Kim H-H, Bae Y, Kim S-H (2013) Galangin attenuates mast cell-mediated allergic inflammation. Food Chem Toxicol 57:209–216
Kim H, Bartley GE, Arvik T, Lipson R, Nah S-Y, Seo K, Yokoyama W (2014) Dietary supplementation of chardonnay grape seed flour reduces plasma cholesterol concentration, hepatic steatosis, and abdominal fat content in high-fat diet-induced obese hamsters. J Agric Food Chem 62:1919–1925
Kim HD, Jeong KH, Jung UJ, Kim SR (2016) Naringin treatment induces neuroprotective effects in a mouse model of Parkinson’s disease in vivo, but not enough to restore the lesioned dopaminergic system. J Nutr Biochem 28:140–146
Kocyigit UM, Taslimi P, Gezegen H, Gulçin İ, Ceylan M (2017a) Evaluation of acetylcholinesterase and carbonic anhydrase inhibition profiles of 1, 2, 3, 4, 6-pentasubstituted-4-hydroxy-cyclohexanes. J Biochem Mol Toxicol 31:e21938
Kocyigit UM, Taşkıran AŞ, Taslimi P, Yokuş A, Temel Y, Gulçin İ (2017b) Inhibitory effects of oxytocin and oxytocin receptor antagonist atosiban on the activities of carbonic anhydrase and acetylcholinesterase enzymes in the liver and kidney tissues of rats. J Biochem Mol Toxicol 31:e21972
Köksal E, Bursal E, Gülçin İ, Korkmaz M, Çağlayan C, Gören AC, Alwasel SH (2017) Antioxidant activity and polyphenol content of Turkish thyme (Thymus vulgaris) monitored by liquid chromatography and tandem mass spectrometry. Int J Food Prop 20:514–525
Kuzu M, Kandemir FM, Yildirim S, Kucukler S, Caglayan C, Turk E (2018) Morin attenuates doxorubicin-induced heart and brain damage by reducing oxidative stress, inflammation and apoptosis. Biomed Pharmacother 106:443–453
Liao X-L, Luo J-G, Kong L-Y (2013) Flavonoids from Millettia nitida var. hirsutissima with their anticoagulative activities and inhibitory effects on NO production. J Nat Med 67:856–861
Mansour HH, Hasan HF (2015) Protective effect of N-acetylcysteine on cyclophosphamide-induced cardiotoxicity in rats. Environ Toxicol Pharmacol 40:417–422
Oyagbemi AA, Omobowale TO, Saba AB, Olowu ER, Dada RO, Akinrinde AS (2016) Gallic acid ameliorates cyclophosphamide-induced neurotoxicity in Wistar rats through free radical scavenging activity and improvement in antioxidant defense system. J Diet Suppl 13:402–419
Qiu L, Cai C, Zhao X, Fang Y, Tang W, Guo C (2017) Inhibition of aldose reductase ameliorates ethanol-induced steatosis in HepG2 cells. Mol Med Rep 15:2732–2736
Schomburg I, Chang A, Schomburg D (2002) BRENDA, enzyme data and metabolic information. NAR 30:47–49
Shokrzadeh M, Ahmadi A, Naghshvar F, Chabra A (2014) Jafarinejhad M (2014): Prophylactic efficacy of melatonin on cyclophosphamide-induced liver toxicity in mice. Biomed Res Int 2014:1–6
Sinanoglu O, Yener AN, Ekici S, Midi A, Aksungar FB (2012): The protective effects of spirulina in cyclophosphamide induced nephrotoxicity and urotoxicity in rats. Urology 80, 1392. e1-1392. e6
Singh C, Prakash C, Tiwari KN, Mishra SK, Kumar V (2018) Premna integrifolia ameliorates cyclophosphamide-induced hepatotoxicity by modulation of oxidative stress and apoptosis. Biomed Pharmacother 107:634–643
Sun L, Luo C, Long J, Wei D, Liu J (2006) Acrolein is a mitochondrial toxin: effects on respiratory function and enzyme activities in isolated rat liver mitochondria. Mitochondrion 6:136–142
Tao Y, Zhang Y, Cheng Y, Wang Y (2013) Rapid screening and identification of α-glucosidase inhibitors from mulberry leaves using enzyme-immobilized magnetic beads coupled with HPLC/MS and NMR. Biomed Chromatogr 27:148–155
Taslimi P, Akıncıoglu H, Gülçin İ (2017a) Synephrine and phenylephrine act as α-amylase, α-glycosidase, acetylcholinesterase, butyrylcholinesterase, and carbonic anhydrase enzymes inhibitors. J Biochem Mol Toxicol 31:e21973
Taslimi P, Caglayan C, Gulcin İ (2017b) The impact of some natural phenolic compounds on carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase, and α-glycosidase enzymes: an antidiabetic, anticholinergic, and antiepileptic study. J Biochem Mol Toxicol 31:e21995
Taslimi P, Aslan HE, Demir Y, Oztaskin N, Maraş A, Gulçin İ, Beydemir S, Goksu S (2018a) Diarylmethanon, bromophenol and diarylmethane compounds: discovery of potent aldose reductase, α-amylase and α-glycosidase inhibitors as new therapeutic approach in diabetes and functional hyperglycemia. Int J Biol Macromol 119:857–863
Taslimi P, Caglayan C, Farzaliyev V, Nabiyev O, Sujayev A, Turkan F, Kaya R, Gulçin İ (2018b) Synthesis and discovery of potent carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase, and α-glycosidase enzymes inhibitors: the novel N, N′-bis-cyanomethylamine and alkoxymethylamine derivatives. J Biochem Mol Toxicol 32:e22042
Taslimi P, Osmanova S, Caglayan C, Turkan F, Sardarova S, Farzaliyev V, Sujayev A, Sadeghian N, Gulçin İ (2018c) Novel amides of 1, 1-bis-(carboxymethylthio)-1-arylethanes: synthesis, characterization, acetylcholinesterase, butyrylcholinesterase, and carbonic anhydrase inhibitory properties. J Biochem Mol Toxicol 32:e22191
Tong J, Mo Q-G, Ma B-X, Ge L-L, Zhou G, Wang Y-W (2017) The protective effects of Cichorium glandulosum seed and cynarin against cyclophosphamide and its metabolite acrolein-induced hepatotoxicity in vivo and in vitro. Food Funct 8:209–219
Topal M, Gülçin İ (2014) Rosmarinic acid: a potent carbonic anhydrase isoenzymes inhibitor. Turk J Chem 38:894–902
Topal M, Gocer H, Topal F, Kalin P, Köse LP, Gülçin İ, Çakmak KC, Küçük M, Durmaz L, Gören AC (2016) Antioxidant, antiradical, and anticholinergic properties of cynarin purified from the Illyrian thistle (Onopordum illyricum L.). J. Enzyme Inhib. Med Chem 31:266–275
Turk E, Kandemir FM, Yildirim S, Caglayan C, Kucukler S, Kuzu M (2018): Protective effect of hesperidin on sodium arsenite-induced nephrotoxicity and hepatotoxicity in rats. Biol. Trace Elem. Res., 1–14
Türkan F, Huyut Z, Taslimi P, Gülçin İ (2018) The effects of some antibiotics from cephalosporin groups on the acetylcholinesterase and butyrylcholinesterase enzymes activities in different tissues of rats. Arch Physiol Biochem 1–7
Türkeş C, Demir Y, Beydemir Ş (2019) Anti-diabetic properties of calcium channel blockers: inhibition effects on aldose reductase enzyme activity. Appl Biochem Biotechnol 1–12
Verpoorte JA, Mehta S, Edsall JT (1967) Esterase activities of human carbonic anhydrases B and C. J Biol Chem 242:4221–4229
Wang M, Barve S, McClain C, Joshi-Barve S (2018) Role of aldose reductase in LPS-inducible intrahepatic immune infiltration and inflammation. FASEB J 32:–832.3
Zarei M, Shivanandappa T (2013) Amelioration of cyclophosphamide-induced hepatotoxicity by the root extract of Decalepis hamiltonii in mice. Food Chem Toxicol 57:179–184
Zhai J, Zhang F, Gao S, Chen L, Feng G, Yin J, Chen W (2018) Schisandra chinensis extract decreases chloroacetaldehyde production in rats and attenuates cyclophosphamide toxicity in liver, kidney and brain. J Ethnopharmacol 210:223–231
Acknowledgments
The author thanks Assist. Prof. Yusuf Temel, Prof. Dr. Fatih Mehmet Kandemir, and Prof. Dr. İlhami Gülçin for their valuable contributions to this study.
Funding
This work was financially supported by Bingol University, Foundation of Scientific Researches Projects (Project number BAPSSHMYO.2016.00.001).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The study was designed and conducted according to ethical norms approved by the Animal Experimentation Ethics Committee of the Bingol University (Bingol, Turkey) (Approval no. 2018-9/2).
Conflict of interest
The author declares that he has no conflict of interest.
Additional information
Responsible editor: Philippe Garrigues
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Caglayan, C. The effects of naringin on different cyclophosphamide-induced organ toxicities in rats: investigation of changes in some metabolic enzyme activities. Environ Sci Pollut Res 26, 26664–26673 (2019). https://doi.org/10.1007/s11356-019-05915-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-019-05915-3