Klorprifos-Etil Uygulanan Diyabetli Ratlarda Likopenin Antioksidan ve Hipoglisemik Etkilerinin Araştırılması

Yıl 2015, Cilt: 8 Sayı: 1, 1 - 17, 01.06.2015

Ruhi Türkmen , Mehmet Özdemir

Öz

Bu çalışmada, klorprifos-etil’in (KP) normal ve diyabetli ratlardaki oksidatif stres ve hiperglisemi üzerine likopenin etkisi araştırıldı. Wistar albino 56 rat kullanıldı. Ratlar her grupta 7 adet olacak şekilde rastgele 8 gruba ayrıldı. Gruplar; Grup 1 kontrol (K) (0,5 ml mısır yağı), Grup 2 diyabet (D) (50 mg/kg streptozotosin (STZ)), Grup 3 klorprifos-etil (KP) (2,7 mg/kg), Grup 4 likopen (L) (10 mg/kg), Grup 5 D+KP, Grup 6 D+L, Grup 7 L+KP, Grup 8 D+L+KP olarak isimlendirildi. Dört haftalık çalışma süresince canlı ağırlıkları ve açlık kan şekeri düzeyleri ölçüldü. Çalışma sonunda tam kanda, malondialdehid (MDA), indirgenmiş glutatyon (GSH) düzeyleri; plazmada, süperoksid dismutaz (SOD), katalaz (CAT), glutatyon peroksidaz (GPx), insülin, asetilkolinesteraz (AkE), nitrik oksid (NO) düzeyleri; serumda ise aspartat aminotransferaz (AST), alanin aminotransferaz (ALT), glikoz, tümor nekrozis faktör-α (TNF-α) ve total antiosidan kapasite (TAK) düzeyleri belirlendi. K grubuyla karşılaştırıldığında STZ ve KP uygulamalarının açlık kan şekeri ve serum glikoz düzeylerini yükselttiği, plazma insülin düzeylerini azalttığı görüldü. Aynı uygulamaların MDA düzeylerini artırdığı, antioksidan enzim aktiviteleri ile birlikte GSH ve TAK düzeylerini ise azalttığı ortaya konuldu. Ayrıca likopenin D grubundaki ratların MDA düzeylerini azalttığı, antioksidan enzim aktiviteleri ile birlikte GSH ve TAK düzeylerini artırdığı tespit edildi. Sonuç olarak likopenin diyabet ve klorprifos-etil tarafından oluşturulan hiperglisemi ve buna bağlı olarak ortaya çıkabilecek komplikasyonların tedavisine yardımcı olabileceği önerilebilir.

Anahtar Kelimeler

Diyabet, Klorprifos-etil, Likopen, Oksidatif stres, Streptozotosin

Investigation of the Hypoglycemic and Antioxidant Effects of Lycopene in Chlorpyrifos-Ethyl Treated Diabetic Rats

Öz

The present study was carried out to investigate the antioxidant and hypoglycemic effect of lycopene (L) on chlorpyrifos-ethyl (CP) induced oxidative stress and hyperglycemia in normal and diabetic rats. Wistar albino 56 adult rats were used. Rats were randomly divided into eight groups, n=7. The groups were called as Group 1 control (C) (0.5 ml corn oil); Group 2 diabetes (D) (50 mg/kg STZ); Group 3 CP (2.7 mg/kg); Group 4 L (10 mg/kg); Group 5 D+CP; Group 6 D+L; Group 7 L+CP; Group 8 D+L+CP. Rat weight gains and fasting blood glucose were measured every week for 4 weeks. At the end of the study, malondialdehyde (MDA) and glutathione (GSH) were assessed in whole blood. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), insulin, acetylcholinesterase (AChE) and nitric oxide (NO) were determined in plasma. The aspartate aminotransferase (AST), alanine aminotransferase (ALT), glucose, tumor necrosis factor-α (TNF-α) and total antioxidant capacity (TAC) were assessed in serum. Treatment of rats with of streptozotocin (STZ) and CP were showed that decreased in plasma insulin level while fasting blood glucose and serum glucose increased compared to the control group. Same treatments were revealed increased in MDA while TAC and GSH levels were decreased with a consistently significant decreased in the activity of antioxidative enzymes. Moreover administration of lycopene to rat in D group was found that decrease in MDA while TAC and GSH levels were increased with a consistently increased in the activity of antioxidative enzymes. This study suggests that lycopene acts as a safe and efficient choice in helper to treatment of diabetes and chlorpyrifos-ethyl induced hyperglycemia and their complications.

Anahtar Kelimeler

Diabetes mellitus, Chlorpyrifos-ethyl, Lycopene, Oxidative stress, Streptozotocine

Kaynakça

• Abdollahi M, Donyavi M, Pournourmohammadi S, Saadat M, Hyperglycemia associated with increased hepatic glycogen phosphorylase and phosphoenolpyruvate carboxykinase in rats following subchronic exposure to malathion.
• Comp Biochem Physiol C Toxicol Pharmacol. 2004b; 137(4):343-347. Abdollahi M, Ranjbar A, Shadnia S, Nikfar S, Rezaie A, Pesticides and oxidative stres: a review. Med Sci Monit. 2004a; 10(6):RA141-147.
• Abou-Seif MA, Youssef AA, Evaluation of some biochemical changes in diabetic patients. Clin Chim Acta. 2004; 346(1):161–170.
• Acker CI, Souza ACG, Dos Santos MP, Mazzanti CM, Nogueira CW, Diphenyl diselenide attenuates hepatic and hematologic toxicity induced by chlorpyrifos acute exposure in rats. Environ Sci Pollut Res. 2012; 19:3481–3490.
• Ahmed MM, Zaki NI, Assessment the ameliorative effect of pomegranate and rutin on chlorpyrifos-ethyl-induced oxidative stress in rats. Nat Sci. 2009; 7(10):49-61.
• Ahmed NS, Mohamed AS, Abdel-Wahhab MA, Chlorpyrifos-induced oxidative stress and histological changes in retinas and kidney in rats: Protective role of ascorbic acid and alpha tocopherol. Pestic. Biochem. Physiol. 2010; 98(1):33-38.
• Aksoy N, Vural H, Sabuncu T, Arslan O, Aksoy S, Beneficial effects of vitamins C and E against oxidative stress in diabetic rats. Nutr Res. 2005; 25(6):625–630.
• Alexandraki K., Piperi C, Ziakas PD, Apostolopoulos NV, Makrilakis K, Syriou V, Diamanti-Kandarakis E, Kaltsas G, Kalofoutis A, Cytokine secretion in long-standing diabetes mellitus type 1 and 2: associations with low-grade systemic inflammation. J Clin Immunol. 2008; 28(4):314-321.
• Ali MM, Agha FG, Amelioration of streptozotocin-induced diabetes mellitus, oxidative stress and dyslipidemia in rats by tomato extract lycopene. Scand J Clin Lab Invest. 2009; 69:371–379.
• Altan N, Dinçel AS, Koca C, Diabetes mellitus and oxidative Stres. Turk J Bioch. 2006; 31(2):51–56.
• Alvarez AA, Ramírez-San Juan E, Canizales-Román A, Chlorpyrifos induces oxidative stress in rats. Toxicol Environ Chem. 2008; 90(5):1019-1025.
• Aly N, El-Gendy K, Mahmoud F, El-Sebae AK, Protective effect of vitamin C against chlorpyrifos oxidative stress in male mice. Pestic Biochem Physiol. 2010; 97(1):7-12.
• Ambali SF, Ameliorative effect of antioxidant vitamins C and E on neurotoxicological, haematological and biochemical changes induced by chronic chlorpyrifos exposure in Wistar rats. PhD Dissertation, Ahmadu Bello University, Zaria, Nigeria. 2009.
• Ambali SF, Ayo JO, Ojo SA, Esievo KA, Vitamin E protects rats from chlorpyrifos-induced increased erythrocyte osmotic fragility in Wistar rats. Food Chem Toxicol. 2010; 48(12):3477-3480.
• Anwar MM, Meki AR, Oxidative stress in streptozotocin-induced diabetic rats: effects of garlic oil and melatonin, Comp Biochem Physiol A Mol Integr Physiol. 2003; 135(4):539-547.
• Ashokkumar N, Pari L, Ramkumar KM, N-Benzoyl-D-phenylalanine attenuates brain acetylcholinesterase in neonatal streptozotocin-diabetic rats. Basic Clin Pharmacol Toxicol. 2006; 99:246–250.
• Astaneie F, Afshari M, Mojtahedi A, Mostafalou S, Zamani MJ, Larijani B, Abdollahi M, Total antioxidant capacity and levels of epidermal growth factor and nitric oxide in blood and saliva of insulin-dependent diabetic patients. Arch Med Res. 2005; 36(4):376-381.
• Atessahin A, Karahan I, Turk G, Gur S, Yilmaz S, Ceribas AO, Protective role of lycopene on cisplatin induced changes in sperm characteristics, testicular damage and oxidative stress in rats. Reprod Toxicol. 2006; 21:42–47.
• Aydın M, Çelik S, Effects of lycopene on plasma glucose, insulin levels, oxidative stress, and body weights of streptozotocin-induced diabetic rats. Turk J Med Sci. 2012; 42(Sup 2):1406-1413
• Bebe FN, Panemangalore M, Exposure to low doses of endosulfan and chlorpyrifos modifies endogenous antioxidants in tissues of rats. J Environ Sci Health B. 2003; 38(3):349-363.
• Beutler E, Duron O, Kelly BM, Improved method for the determination of blood glutathione. J Lab Clin Med. 1963; 61:882-888.
• Bukowska B, 2,4,5-T and 2,4,5-TCP induce oxidative damage in human erythrocytes: the role of glutathione. Cell Biol Int. 2004; 28(7):557-563.
• Can M, Diabetik ratlarda pufa alımınının hipokampus NMDA reseptör subünit konsantrasyonları ve lipid peroksidasyonu üzerine etkisi. Tıpta Uzmanlık Tezi. Süleyman Demirel Üniv. Tıp Fakültesi Biyokimya Anabilim Dalı, Isparta. 2003. Cathcart RF, Vitamin C: the nontoxic, nonrate-limited, antioxidant free radical scavenger. Med Hypotheses. 1985; 18:61-77.
• Ceriello A, New insights on oxidative stress and diabetic complications may lead to a “causal” antioxidant therapy. Diabetes Care. 2003; 26(5): 1589–1596.
• Chhabra SK, Hashim S, Rao AR, Modulation of hepatic glutathione system of enzymes in suckling mouse pups exposed translactionally to malathion. J Appl Toxicol. 1993; 13:411–416.
• Ching S, Ingram D, Hahnel R, Beilby J, Rossi E, Serum levels of micronutrients, antioxidants and total antioxidant status predict risk of breast cancer in a case control study. J Nutr. 2002; 132:303–306.
• Civen M, Brown CB, Morin RJ, Effects of organophosphate insecticides on adrenal cholesteryl ester and steroid metabolism. Biochem Pharmacol. 1977; 26(20):1901-1907.
• Çömelekoğlu Ü, Mazmancı B, Pestisidlerin kronik etkisine maruz kalan tarım işçilerinde karaciğer fonksiyonlarının incelenmesi. Turk J Biol. 2000; 24:461–466.
• Demir F, Uzun FG, Durak D, Kalender Y, Subacute chlorpyrifos-induced oxidative stress in rat erythrocytes and the protective effects of catechin and quercetin. Pestic Biochem Physiol. 2011; 99:77-81.
• Draper HH, Hadley M, Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol. 1990; 186:421-431.
• Düzgüner V, Deneysel olarak diyabet oluşturulan tavşanlarda çinkonun lipid peroksidasyonu ve antioksidan sistem üzerine etkisi.Yüksek Lisans Tezi. Mustafa Kemal Üniv. Sağlık Bilimleri Enstitüsü, Hatay. 2005.
• Duzguner V, Kucukgul A, Erdogan S, Celik S, Sahin K, Effect of lycopene administration on plasma glucose, oxidative stress and body weight in streptozotocin diabetic rats. J Appl Anim Res. 2008; 33:17-20.
• Dyer AM, Effects of an organophosphate pesticide (chlorpyrifos) on sprague-Dawley body weight in correlation to high fat diet and forced exercise. PhD Thesis. Department of Environmental Science Allegheny College, Meadville, Pensylvania. 2011
• Ecobichon DJ, Toxic Effects of Pesticides. Casarett & Doull's Toxicology The Basic Science of Poisons. Ed; Klaassen CD, 6th Ed. McGraw-Hill, New York. 2001; pp.763-810.
• El-Banna SG, Attia AM, Hafez AM, El-Kazaz SM, Effect of garlic consumption on blood lipid and oxidant/antioxidant parameters in rat males exposed to chlorpyrifos. Slovak J Anim Sci. 2009; 42(3):111-117.
• Elelaimy IA, Ibrahim HM, Ghaffar FRA, Alawthan YS, Evaluation of sub-chronic chlorpyrifos poisoning on immunological and biochemical changes in rats and protective effect of eugenol. JAPS. 2012; 02(06):51-61.
• El-Missiry MA, El-Gindy AM, Amelioration of alloxan induced diabetes mellitus and oxidative stress in rats by oil of Eruca sativa seeds. Ann Nutr Metab. 2000; 44:97–100.
• Fukuhara M, Matsumura K, Wakisaka M, Takata Y, Sonoki K, Fujisawa K, Ansai T, Akifusa S, Fujii K, Lida M, Takehara T, Hyperglycemia promotes microinflammation as evaluated by C reactive protein in the very elderly. Intern Med. 2007; 46(5):207–212.
• Ghareeb DA, Hussen HM, Vanadium improves brain acetylcholinesterase activity on early stage alloxan-diabetic rats. Neurosci Lett. 2008; 436:44–47.
• Goel A, Dani V, Dhawan DK, Protective effects of zinc on lipid peroxidation, antioxidant enzymes and hepatic histoarchitecture in chlorpyrifos-induced toxicity. Chem Biol Interact. 2005; 156(2–3):131–140.
• Gordon CJ, Rowsey PJ, Are circulating cytokines interleukin-6 and tumor necrosis factor alpha involved in chlorpyrifos-induced fever? Toxicology. 1999; 134:9-17.
• Gupta RC, Milatovic D, Dettbarn WD, Nitric oxide modulates high-energy phosphates in brain regions of rats intoxicated with diisopropylphosphorofluoridate or carbofuran: prevention by N-tert-butyl-alpha-phenylnitrone or vitamin E. Arch Toxicol. 2001; 75(6):346-356.
• Icenogle LM, Christopher NC, Blackwelder WP, Caldwell DP, Qiao D, Seidler FJ, Slotkin TA, Lewin ED, Behaviroal alterations in adolescent and adult rats caused by a brief subtoxic exposure to chlorpyrifos during neurulation. Neurotoxicol Teratol. 2004; 26(1):95-101.
• Iyer P, Kaufman F, Wu KL, Pharmacokinetics and Metabolism. In: Evidence on the Developmental and Reproductive Toxicity of Chlorpyrifos. Reproductive and Cancer Hazard Assessment Branch Office of Environmental Health Hazard Assessment California.Environmental Protection Agency, 2008; pp. 7-12.
• Johansen JS, Harris AK, Rychly DJ, Ergul A, Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice. Cardiovasc Diabetol. 2005; 4(1):5. doi:10.1186/1475-2840-4-5
• Kağa S, Streptozotozin ile diyabet oluşturulan sıçanlarda papatya (Matricaria Chamomilla L.) ekstresinin antidiabetik ve antioksidatif etkisinin araştırılması. Yüksek Lisans Tezi, Afyon Kocatepe Üniv. Sağlık Bilimleri Enstitüsü, Afyonkarahisar. 2006.
• Kamath V, Rajini PS, Altered glucose homeostasis and oxidative impairment in pancreas of rats subjected to dimethoate intoxication. Toxicology. 2007; 231:137-146.
• Kamboj SS, Chopra K, Sandhir R, Neuroprotective effect of N-acetylcysteine in the development of diabetic encephalopathy in streptozotocin-induced diabetes. Metab Brain Dis. 2008; 23(4):427-443.
• Kaneto H, Xu G, Song KH, Suzuma K, Bonner-Weir S, Sharma A, Weir GC, Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function through the induction of oxidative stress. J Biol Chem. 2001; 276(33):31099–31104.
• Karanth S, Pope C, Age-related effects of chlorpyrifos and parathion on acetylcholine synthesis in rat stiatum. Neurotoxicol Teratol. 2003; 25(5):599-606.
• Kaya S, Genel Anestezikler. Veteriner Farmakoloji, Cilt 1, 4. Baskı. Ed; Kaya S, Medisan Yayınları, Ankara. 2006; sy. 181-330.
• Khalifa FK, Khalil FA, Barakat HA, Hassan MM, Protective role of wheat germ and grape seed oils in chlorpyrifos-induced oxidative stress, biochemical and histological alterations in liver of rats. Aust J Basic Appl Sci. 2011; 5(10):54-66.
• Kowluru RA, Kanwar M, Effects of curcumin on retinal oxidative stress and inflammation in diabetes. Nutr Metabol (Lond). 2007; 16:4–8.
• Kuhad A, Chopra K, Curcumin attenuates diabetic encephalopathy in rats: behavioral and biochemical evidences. Eur J Pharmacol. 2007; 576(1-3):34–42.
• Kuhad A, Chopra K, Effect of sesamol on diabetes-associated cognitive decline in rats. Exp Brain Res. 2008; 185(3):411-420.
• Kuhad A, Sethi R, Chopra K, Lycopene attenuates diabetes-associated cognitive decline in rats. Life Sci. 2008a; 83:128-134.
• Kuhad A, Sharma S, Chopra K, Lycopene attenuates thermal hyperalgesia in a diabetic mouse model of neuropathic pain. Eur J Pain. 2008b; 12(5):624-632.
• Laight DW, Carrier MJ, Anggard EE, Antioxidants, diabetes and endothelial dysfunction. Cardiovas Res. 2000; 47:457-464.
• Lassiter TL, Brimijoin S, Rats gain excess weight after developmental exposure to the organophosphate pesticide, chlorpyrifos. Neurotoxicol Teratol. 2008; 30(2):125-130.
• Lei YC, Hwang JS, Chan CC, Lee CT, Cheng TJ, Enhanced oxidative stress and endothelial dysfunction in streptozotocin-diabetic rats exposed to fine particles. Environ Res. 2005; 99(3):335-343.
• Lenzen S, The mechanisms of alloxan and streptozotocin-induced diabetes. Diabetologia. 2008; 51:216–226.
• Li BH, Zhang QX, Dong DJ, Lin XM, Effect of lycopene on immunity in rats with acute lung injury. Beijing Da Xue Xue Bao. 2007; 39:77–82.
• Lowinson JH, Ruiz P, Millman RB, Langrod JG, Substance Abuse: A Comprehensive Textbook. 4th Ed. Lippincott Williams & Wilkins, Philadelphia, USA. 2005; pp. 479-481.
• Mamdouh MA, Fatma GA, Amelioration of streptozotocin-induced diabetes mellitus, oxidative stres and dyslipidemia in rats by tomato extract lycopene. Scand J Clin Lab Invest. 2009; 69(3):371-379.
• Mansour SA, Mossa AH, Lipid peroxidation and oxidative stress in rat erythrocytes induced by chlorpyrifos and the protective effect of zinc. Pestic Biochem Physiol. 2009; 93:34–39.
• Mansour SA, Mossa AH, Oxidative damage, biochemical and histological alterations in rats exposed to chlorpyrifos and the antioxidant role of zinc. Pestic Biochem Physiol. 2010; 96:14-23.
• Mellert W, Deckardt K, Gembardt C, Schulte S, Van Ravenzwaay B, Slesinski RS, Thirten-week oral toxicity study of synthetic lycopene products in rats. Food Chem Toxicol. 2002; 40(11):1581-1588.
• Messarah M, Boumendjel A, Chouabia A, Klibet F, Abdennour C, Boulakoud MS, El Feki A, Influence of thyroid dysfunction on liver lipid peroxidation and antioxidant status in experimental rats. Exp Toxicol Pathol. 2010; 62(3):301-310.
• Panahi P, Vosough-Ghanbari S, Pournourmohammadi S, Ostad SN, Nikfar S, Minaie B, Abdollahi M, Stimulatory effects of malathion on the key enzymes activities of insulin secretion in langerhans islets, glutamate dehydrogenase and glucokinase. Toxicol Mech Methods. 2006; 16(4):161-167.
• Pourkhalili N, Pournourmohammadi S, Rahimi F, Vosough-Ghanbari S, Baeeri M, Ostad SN, Abdollahi M, Comparative effects of calciumchannel blockers, autonomic nervous system blockers, and free radicalscavengers on diazinon-induced hyposecretion of insulin from isolated islets of langerhans in rats, Arh Hig Rada Toxicol. 2009; 60(2):157-164.
• Pournourmohammadi S, Farzami B, Ostad SN, Azizi E, Abdollahi M, Effects of malathion subchronic exposure on rat skeletal muscle glucose metabolism. Environ Toxicol Pharmacol. 2005; 19(1):191-196.
• Praticò D, Antioxidants and endothelium protection. Atherosclerosis. 2005; 181(2):215–224.
• Rajasekaran S, Ravi K, Sivagnanam K, Subramanian S, Beneficial effects of aloe vera leaf gel extract on lipid profile status in rats with streptozotocin diabetes. Clin Exp Pharmacol Physiol. 2006; 33(3):232-237.
• Rao AV, Rao LG, Carotenoids and human health. Pharmacol Res. 2007; 55:207-216.
• Riso P, Visioli F, Grande S, Guarnieri S, Gardana C, Simonetti P, Porrini M, Effect of a tomato based drink on markers of inflammation, immunomodulation, and oxidative stress. J Agric Food Chem. 2006; 54:2563–2566.
• Rowsey PJ, Gordon CJ, Tumor necrosis factor is involved in chlorpyrifos-induced changes in core temperature in the female rat. Toxicol Lett. 1999; 109:51-59.
• Sancheti, S., Sancheti, S., Seo, SY., Antidiabetic and antiacetylcholinesterase effects of ethyl acetate fraction of Chaenomeles sinensis (Thouin) Koehne fruits in streptozotocin induced diabetic rats. Exp Toxicol Pathol. 2013; 65(1-2):55-60.
• Saxena R, Garg P, Jain DK, In vitro anti-oxidant effect of vitamin E on oxidative stress induced due to pesticides in rat erythrocytes. Toxicol Int. 2011; 18(1):73–76.
• Schmatz R, Mazzanti CM, Spanevello R, Stefanello N, Gutierres J, Corrêa M, Da Rosa MM, Rubin MA, Chitolina Schetinger MR, Morsch VM, Resveratrol prevents memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic rats. Eur J Pharmacol. 2009; 610(1-3):42-48.
• Seifert J, Toxicologic significance of the hyperglycemia caused by organophosphorus insecticides. Bull Environ Contamin Toxicol. 2001; 67(1):463-469.
• Shadnia S, Azizi E, Hosseini R, Khoei S, Fouladdel S, Pajoumand J, Jalali N, Abdollahi M, Evaluation of oxidative stres and genotoxicity in organophosphorus insecticide formulators. Hum Exp Toxicol. 2005; 24(9):439-445.
• Sharma S, Chopra K, Kulkarni SK, Effect of insulin and its combination with resveratrol or curcumin in attenuation of diabetic neuropathic pain: participation of nitric oxide and TNF-alpha. Phytother Res. 2007; 21:278–283.
• Shittu M, Ayo JO, Ambali SF, Fatihu MY, Onyeanusi BI, Kawu MU, Chronic chlorpyrifos-induced oxidative changes in the testes and pituitary gland of Wistar rats: Ameliorative effects of vitamin C. Pestic Biochem Physiol. 2012; 102(1):79-85.
• Tapiero H, Townsend DM, Tew KD, The role of carotenoids in the prevention of human pathologies. Biomed Pharmacother. 2004; 58(2):100-110.
• Tian L, Cai Q, Wei H, Alterations of antioxidant enzymes and oxidative damage to macromolecules in different organs of rats during aging. Free Radic Biol Med. 1998; 24(9):1477-1484.
• Tiedge M, Lortz S, Drinkgern J, Lenzen S, Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes. 1997; 46(11):1733-1742.
• Tripathi S, Srivastav AK, Nephrotoxicity induced by long-term oral administration of different doses of chlorpyrifos, Toxicol Ind Health. 2010; 26(7):439-447.
• Tsakiris S, Effects of L-phenylalanine on acetylcholinesterase and Na (+), K (+)-ATPase activities in adult and aged rat brain. Mech Ageing Dev. 2001; 122:491–501.
• Turk G, Atessahin A, Sonmez M, Yuce A, Ceribas AO, Lycopene protects against cyclosporine A-induced testicular toxicity in rats. Theriogenology. 2007; 67:778–785.
• Türkmen R, Özdemir M, Diabetes mellitus’ta serbest radikallerin rolü. Kocatepe Vet J. 2011; 4(1):65-72. Tuzcu M, Baydas G, Effect of melatonin and vitamin E on diabetes-induced learning and memory impairment in rats. Eur J Pharmacol. 2006; 537(1-3):106–110.
• Uchiyama S, Yamaguchi M, Oral administration of beta-cryptoxanthin prevents bone loss in streptozotocin-diabetic rats in vivo. Biol Pharm Bull. 2005; 28(9):1766-1769.
• Ural MS, Chlorpyrifos-induced changes in oxidant/antioxidant status and haematological parameters of Cyprinus carpio carpio: Ameliorative effect of lycopene. Chemosphere. 2013; 90:2059-2064.
• Uzun FG, Demir F, Kalender S, Bas H, Kalender Y, Protective effect of catechin and quercetin on chlorpyrifos-induced lung toxicity in male rats. Food Chem Toxicol. 2011; 48(6):1714-1720.
• Uzun FG, Kalender Y, Chlorpyrifos induced hepatotoxic and hematologic changes in rats: The role of quercetin and catechin. Food Chem Toxicol. 2013; 55:549–556.
• Velazquez E, Winocour PH, Kesteven P, Alberti KG, Laker MF, Relation of lipid peroxides to macrovascular disease in type 2 diabetes. Diabet Med. 1991; 8:752–758.
• Venkateswaran S, Pari L, Effect of Coccinia indica leaves on antioxidant status in streptozotocin-induced diabetic rats. J Ethnopharmacol. 2003; 84(2-3):163-168.
• Verma RS, Mehta A, Srivastava N, In vivo chlorpyrifos induced oxidative stress: Attenuation by antioxidant vitamins. Pestic Biochem Physiol. 2007; 88:191-196.
• Wang HP, Liang YJ, Long DX, Chen JX, Hou WY, Wu YJ, Metabolic profiles of serum from rats after subchronic exposure to chlorpyrifos and carbaryl. Chem Res Toxicol. 2009; 22:1026-1033.
• Xia Z, Nagareddy PR, Guo Z, Zhang W, Mcneill JH, Antioxidant N-acetylcysteine restores systemic nitric oxide availability and corrects depressions in arterial blood pressure and heart rate in diabetic rats. Free Radic Res. 2006; 40(2):175–184.
• Yan Z, Characterization of chlorpyrifos toxicity on the pancreatic beta cell line RINM5F, Doctoral dissertation, Wright State University, USA. 2010.
• Yano BL, Young JT, Mattson JL, Lack of carcinogenicity of chlorpyrifos insecticide in a high-dose, 2-year dietary toxicity study in Fischer 344 rats. Toxicol Sci. 2000; 53:135-144. Yardim-Akaydın S, Sepici A, Ozkan Y, Simsek B, Sepici V, Evaluation of allontoin levels as a new marker of oxidative stress in Behçet’s disease. Scand J Rheumatol. 2006; 35(1):61-64.
• Yegin SC, Yur F, Ceylan E, Effect of lycopene application in rats with experimental diabetes using lipoprotein, paraoxonase and cytokines. J Membrane Biol. 2013; 246:621–626.
• Yilmaz S, Atessahin A, Sahna E, Karahan I, Ozer S, Protective effect of lycopene on adriamycin-induced cardiotoxicity and nephrotoxicity. Toxicology. 2006; 218:164–171.
• Yonar ME, The effect of lycopene on oxytetracycline-induced oxidative stress and immunosuppression in rainbow trout (Oncorhynchus mykiss, W.). Fish Shellfish Immunol. 2012; 32:994–1001.
• Yu F, Wang Z, Ju B, Wang Y, Wang J, Bai D, Apoptotic effect of organophosphorus insecticide chlorpyrifos on mouse retina in vivo via oxidative stress and protection of combination of vitamins C and E. Exp Toxicol Pathol. 2008; 59(6):415-423.
• Zhou JF, Xu GB, Fang WJ, Relationship between acute organophosphorus pesticide poisoning and damages induced by free radicals. Biomed Environ Sci. 2002; 15(2):177-186.
• Zhu J, Wang C, Xu Y, Lycopene attenuates endothelial dysfunction in streptozotocin-induced diabetic rats by reducing oxidative stress. Pharm Biol. 2011; 49(11):1144–1149.