HİDAYET METİN ERDOĞAN, Mehmet ÇİTİL, MEHMET TUZCU, Emine ATAKİŞİ, Vehbi GÜNEŞ, ERDOĞAN UZLU

The effect of L-carnitine administration on doxorubicine induced hepatoxicity and nephrotoxicity in rabbits

Bu çalışma doksorubisin (DOX) kaynaklı karaciğer ve böbrek hasarlarında L-carnitinin koruyucu etkilerinin araştırılması için tasarlanmıştır. Toplam 21 adet sağlıklı Yeni Zelanda ırkı albino tavşan 3 gruba ayrıldı. I. Gruptaki tavşanlara (n=8) 0.6 mg/kg/canlı ağırlık (CA) dozunda DOX intraperitoneal (IP) olarak 6 gün boyunca verildi, II. Gruptaki hayvanlara (n=7) 0.6 mg/kg/CA dozunda DOX, IP olarak ve 1000 mg/kg/CA dozunda LCAR, IP olarak 6 gün boyunca verildi ve III. Gruptakilere (n=6) ise 1000 mg/kg/CA dozunda LCAR, IP olarak 6 gün boyunca verildi. Çalışmanın başlangıcında (ilaç uygulamadan önce) ve ilaç uyguladıktan iki saat sonra 6 gün boyunca tüm hayvanların vena auricularislerinden kan örnekleri alındı. Çalışmanın sonunda ise tüm hayvanların histopatolojik muayeneleri yapıldı. Sadece DOX uygulanan tavşanlarda histopatolojik muayenelerde karaciğer ve böbreklerde şiddetli hasarlar tespit edildi. Diğer gruplara nazaran DOX grubundaki serum ALT, AST, üre ve kreatin konsantrasyonlarındaki önemli artış histopatolojik bulguları teyit etti. Histopatolojik ve biyokimyasal analizler paranteral LCAR uygulamasının karaciğer ve böbrekteki DOX kaynaklı yan etkilere karşı olası koruyucu role sahip olduğunu ortaya koymuştur.

Anahtar Kelimeler:

böbrek toksisitesi, karaciğer, histopatoloji, böbrekler, doksorubisin, toksisite, tavşan, koruma, yan etkiler

L-carnitin uygulamasının tavşanlarda doksorubisin kaynaklı hepatopatoksisite ve nefrotoksisite üzerine etkisi

This study was designed to investigate the protective effect of L-carnitine (LCAR) on doxorubicin (DOX) associated damage in liver and kidney. A total of 21 healthy albino New-Zealand rabbits were divided into 3 groups. Rabbits in group I (n=8) received DOX at the dose of 0.6 mg/kg/day body weight (BW) intraperitoneally (IP) for 6 days, group II (n=7) received DOX at the dose of 0.6 mg/kg/day BW, IP and LCAR at the dose of 1000 mg/kg/day BW IP for 6 days and group III (n=6) received LCAR at dose of 1000 mg/kg/day BW IP for 6 days. Blood samples from auricular vein were taken from all animals at the beginning of the experiment (before the drug administration) and 2 hours after the drug administration daily for 6 days. Histopathological examination of all animals was carried out at the end of the study. Severe alterations in liver and kidney of rabbits given only DOX were noticed on histopathology examination. This was supported by marked increases in serum concentrations of ALT, AST, creatinin, and urea in this group when compared to other groups. The results of histopathological and biochemical analysis revealed that parenteral LCAR has a potential role in protection against adverse effect of DOX on liver and kidney.

Keywords:

nephrotoxicity, liver, histopathology, kidneys, doxorubicin, toxicity, rabbits, protection, adverse effects,

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1. Santos RVT, Batirsta Jr ML, Caperuto EC, Costa Rosa LFBP: Chronic supplementation of creatine and vitamins C and E increases survival and improves biochemical parameters after doxorubicin treatment in rats. Clin Exp Pharmacol Physiol, 34, 1294-1299, 2007.
2.Kalender Y, Yel M, Kalender S: Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats. The effects of vitamin E and catechin. Toxicology, 209, 39-45, 2005.
3.El-Missiry MA, Othman AI, Amer MA, Abd El-Aziz MA: Attenuation of the acute adriamycin-induced cardiac and hepatic oxidative toxicity by N-(2-mercaptopropionyl) glycine in rats. Free Radic Res, 35, 575-581, 2001.
4.Zhang J, Clark JR, Herman EH, Ferrans VJ: Doxorubicininduced apoptosis in spontaneously hypertensive rats: Differential effects in heart, kidney and intestine, and inhibition by ICRF-187. J Mol Cell Cardiol, 28, 1931-1943, 1996.
5.Quiles JL, Huertas JR, Battino M, Mataix J, Ramirez-Tortosa MC: Antioxidant nutrients and adriamycin toxicity. Toxicology, 180, 79-95, 2002.
6.Luo X, Reichetzer B, Trines J, Benson LN, Lehotay DC: Lcarnitine attenuates doxorubicin-induced lipid peroxidation in rats. Free Radic Biol Med, 26 (9-10): 1158-1165, 1999.
7.Gianni L, Myers CE: The Role of Free Radical Formation in the Cardiotoxicity of Anthracycline. In, Muggia FM, Green MD, Speyer JL (Eds): Cancer Treatment and the Heart. pp. 9 46. The John Hopkins University Press, Baltimore, 1992.
8.Plaa GL, Witschi H: Chemicals, drugs and lipid per-oxidation. Annu Rev Pharmacol Toxicol, 16, 125-141, 1976.
9.Citil M, Erdogan HM, Uzlu E, Atakisi E, Gunes V, Tuzcu M, Uzun M, Doğan A: Protective effects of L-carnitine on doxorubicine induced cardiomyopathy in rabbits. Kafkas Univ Vet Fak Derg, 14 (2): 229-235, 2008.
10.Boonsanit D, Kanchanapangka S, Buranakarl C: Lcarnitine ameliorates doxorubicin-induced nephrotic syndrome in rats. Nephrology, 11, 313-320, 2006.
11.Karapehlivan M, Uzlu E, Atakisi O, Erdogan HM, Uzun M, Citil M: Doksorubisin uygulanan tavsanlarda plazma sialik asit, malondialdehit ve redükte glutatyon düzeylerine Lkarnitinin etkileri. Kafkas Univ Vet Fak Derg, 13 (2): 155-160. 2007.
12.Bieber LL: Carnitine. Annu Rev Biochem, 57, 261-283, 1988.
13.Furuno T, Kanno T, Arita K, Asami M, Utsumi T, Doi Y, Inoue M, Utsumi K: Roles of long chain fatty acids and carnitine in mitochondrial membrane permeability transition. Biochem Pharmacol, 62 (8): 1037-1046, 2001.
14.Liu J, Atamna H, Kuratsune H, Ames BN: Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites. Ann N Y Acad Sci, 959, 133-166, 2002.
15.Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, Bartholomew JC, Ames BN: Feeding acetyl-Lcarnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci USA, 99 (4): 1870-1875, 2002.
16.Pastorino JG, Snyder JW, Serroni A, Hoek JB, Farber JL: Cyclosporin and carnitine prevent the anoxic death of cultured hepatocytes by inhibiting the mitochondrial permeability transition. J Biol Chem, 268 (19): 13791-1398, 1993.
17.Kalaiselvi T, Panneersalvam C: Effect of L-carnitine on the status of lipid peroxidation and antioxidants in aging rats. J Nutr Biochem, 9, 575-581, 1998.
18.Arockia Rani PJ, Panneerselvam C: L-carnitine as a free radical scavenger in aging. Exp Gerontol, 36, 1713-1726, 2001.
19.Yagmurca M, Bas O, Mollaoglu H, Sahin O, Nacar A, Karaman O, Songur A: Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats. Arch Med Res, 38 (4): 380-385, 2007.
20.Injac R, Perse M, Obermajer N, Djordjevic-Milic V, Prijatelj M, Djordjevic A, Cerar A, Strukelj B: Potential hepatoprotective effects of fullerenol C60(OH)24 in doxorubicin-induced hepatotoxicity in rats with mammary carcinomas. Biomaterials, 29, 3451-3460, 2008.
21.Gokcimen A, Cim A, Tola HT, Bayram D, Kocak A, Ozguner F, Ayata A: Protective effect of N-acetylcysteine, caffeic acid and vitamin E on doxorubicin hepatotoxicity. Hum Exp Toxicol, 26, 519-525, 2007.
22.Kwiecien I, Michalska M, Wlodek L: The selective effect of cystathionine on doxorubicin hepatotoxicity in tumor-bearing mice. Eur J Pharmacol, 550, 39-46, 2006.
23.Teraoka K, Hirano M, Yamaguchi K, Yamashina A: Progressive cardiac dysfunction in adriamycin-induced cardiomyopathy rats. Eur J Heart Fail, 2, 373-378 2000.
24. Zhou S, Starkov A, Froberg MK, Leino RL, Wallace KB: Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res, 61, 771777, 2001.
25.Pedrycz A, Wieczorski M, Czerny K: The influence of a single dose of adriamycin on the pregnant rat female liver-histological and histochemical evaluation. Ann Univ Mariae Curie Sklodowska, 59, 319-323, 2004.
26.Zeidan Q, Strauss M, Porras N, Anselmi G: Differential long term subcellular response to heart and liver to adriamycin stress. J Submicrosc Cytol Pathol, 34, 315-321, 2002.
27.Kumar D, Kirshenbaum L, Li T, Danelisen I, Singal P: Apoptosis in isolated adult cardiomyocytes exposed to adriamycin. Ann N Y Acad Sci, 874, 156-168, 1999.
28.Andrieu-Abadie N, Jaffrezou JP, Hatem S, Laurent G, Levade T, Mercadier JJ: L-carnitine prevents doxorubicininduced apoptosis of cardiac myocytes: Role of inhibition of ceramide generation. FASEB J, 13, 1501-1510, 1999.
29.Mansour MA, El-Kashef HA, Al-Shabanah OA: Effect of captopril on doxorubicin-induced nephrotoxicity in normal rats. Pharmacol Res, 39 (3): 233-237, 1999.
30.Pedrycz A, Wieczorski M, Czerny K: Increased apoptosis in the adult rat liver after a single dose of adriamycin administration. Ann UMCS Sect D, 59, 313-318, 2004.
31.Pedrycz A, Boratynski Z, Wieczorski M, Visconti J: Ultrastructural and immunohistochemical evaluation of apoptosis in foetal rat liver after adriamycin administration. Bull Vet Inst Pulawy, 49, 475-479, 2005.
32.Griffin Green EA, Zaleska MM, Erecsinska M: Adriamycin induced lipid peroxidation in mitochondria and microsomes. Biochem Pharmacol, 37, 3071-3077, 1988.
33.Di Marzio L, Alesse E, Roncaioli P, Muzi P, Moretti S, Marcellini S, Amicosante G, De Simone C, Cifone MG: Influence of L-carnitine on CD95 cross-linking-induced apoptosis and ceramide generation in human cell lines: Correlation with its effects on purified acidic and neutral sphingomyelinases invitro. Proc Assoc Am Physicians, 109, 154-163, 1997.