Skip to content
BY-NC-ND 3.0 license Open Access Published by De Gruyter Open Access March 27, 2009

Protective effect of L-carnitine against cisplatin-induced liver and kidney oxidant injury in rats

Kerim Cayir, Ali Karadeniz, Abdulkadir Yildirim, Yildiray Kalkan, Akar Karakoc, Mustafa Keles and Salim Tekin
From the journal Open Medicine

Abstract

The present study was designed to investigate the protective effects of L-carnitine (LC) on changes in the levels of lipid peroxidation and endogenous antioxidants induced by cisplatin (cis-diamminedichloroplatinum II, CDDP) in the liver and kidney tissues of rats. Twenty-four Sprague Dawley rats were equally divided into four groups of six rats each: control, cisplatin, L-carnitine, and L-carnitine plus cisplatin. The degree of protection produced by L-carnitine was evaluated by determining the level of malondialdehyde (MDA). The activity of glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione S-transferase (GST), and superoxide dismutase (SOD) were estimated from liver and kidney homogenates, and the liver and kidney were histologically examined as well. L-carnitine elicited significant liver and kidney protective activity by decreasing the level of lipid peroxidation (MDA) and elevating the activity of GSH, GSHPx, GST, and SOD. Furthermore, these biochemical observations were supported by histological findings. In conclusion, the present study indicates a significant role for reactive oxygen species (ROS) and their relation to liver and kidney dysfunction, and points to the therapeutic potential of LC in CDDP-induced liver and kidney toxicity.

[1] Cella D.F., Measuring quality of life in palliative care. Semin. Oncol., 1995, 22 (2 Suppl 3), 73–81 10.1007/BF00343916Search in Google Scholar

[2] World Health Organization. Cancer pain relief and palliative care: Report of a WHO expert committee (Technical Report Series 804). Geneva, Switzerland: WHO, 1990. Search in Google Scholar

[3] Turk G., Atessahin A., Sonmez M., Ceribasi A.O., Yuce A., Improvement of cisplatin-induced injuries to sperm quality, the oxidant-antioxidant system, and the histologic structure of the rat testis by ellagic acid. Fertil. Steril., 2008 89, 1474–1481 http://dx.doi.org/10.1016/j.fertnstert.2007.04.05910.1016/j.fertnstert.2007.04.059Search in Google Scholar

[4] Gottfried M., Ramlau R., Krzakowski M., Ziolo G., Olechnowicz H., Koubkova L. et al., Cisplatin-based three drugs combination (NIP) as induction and adjuvant treatment in locally advanced non-small cell lung cancer: final results. J. Thorac. Oncol., 2008 3, 152–157 http://dx.doi.org/10.1097/JTO.0b013e318160c0e710.1097/JTO.0b013e318160c0e7Search in Google Scholar

[5] Liao Y., Lu X., Lu C., Li G., Jin Y., Tang H., Selection of agents for prevention of cisplatin-induced hepatotoxicity. Pharmacol. Res., 2008 57, 125–131 http://dx.doi.org/10.1016/j.phrs.2008.01.00110.1016/j.phrs.2008.01.001Search in Google Scholar

[6] Tarladacalisir Y.T., Kanter M., Uygun, M., Protective effects of vitamin C on cisplatin-induced renal damage: a light and electron microscopic study. Ren. Fail., 2008 30, 1–8 http://dx.doi.org/10.1080/0886022070174207010.1080/08860220701742070Search in Google Scholar

[7] Naziroglu M., Karaoglu A., Aksoy A.O., Selenium and high dose vitamin E administration protects cisplatininduced oxidative damage to renal, liver and lens tissues in rats. Toxicology, 2004 195, 221–230 http://dx.doi.org/10.1016/j.tox.2003.10.01210.1016/j.tox.2003.10.012Search in Google Scholar

[8] Koc A., Duru M., Ciralik H., Akcan R., Sogut S., Protective agent, erdosteine, against cisplatininduced hepatic oxidant injury in rats. Mol. Cell Biochem., 2005 278, 79–84 http://dx.doi.org/10.1007/s11010-005-6630-z10.1007/s11010-005-6630-zSearch in Google Scholar

[9] Iseri S., Ercan F., Gedik N., Yuksel M., Alican I., Simvastatin attenuates cisplatin-induced kidney and liver damage in rats. Toxicology, 2007 230, 256–264 http://dx.doi.org/10.1016/j.tox.2006.11.07310.1016/j.tox.2006.11.073Search in Google Scholar

[10] Tikoo K., Tamta A., Ali I.Y., Gupta J., Gaikwad A.B., Tannic acid prevents azidothymidine (AZT) induced hepatotoxicity and genotoxicityalong with change in expression of PARG and histone H3 acetylation. Toxicol. Lett., 2008 177, 90–96 http://dx.doi.org/10.1016/j.toxlet.2007.12.01210.1016/j.toxlet.2007.12.012Search in Google Scholar

[11] Nath K.A., Norby S.M., Reactive oxygen species and acute renal failure. Am. J. Med., 2000 109, 665–678. http://dx.doi.org/10.1016/S0002-9343(00)00612-410.1016/S0002-9343(00)00612-4Search in Google Scholar

[12] Lynch E.D., Gu R., Pierce C., Kil J., Combined oral delivery of ebselen and allopurinol reduces multiple cisplatin toxicities in rat breast and ovarian cancer models while enhancing anti-tumoractivity. Anticancer Drugs, 2005 16, 569–579 http://dx.doi.org/10.1097/00001813-200506000-0001310.1097/00001813-200506000-00013Search in Google Scholar

[13] Al-Majed A.A., Carnitine deficiency provokes cisplatin-induced hepatotoxicity in rats. Basic Clin. Pharmacol. Toxicol., 2007 100, 145–150 http://dx.doi.org/10.1111/j.1742-7843.2006.00024.x10.1111/j.1742-7843.2006.00024.xSearch in Google Scholar

[14] Aleisa A.M., Al-Majed A.A., Al-Yahya A.A., Al-Rejaie S.S., Bakheet S.A., Al- Shabanah O.A. et al., Reversal of cisplatin-induced carnitine deficiency and energy starvation by propionyl-L-carnitine in rat kidney tissues. Clin. Exp. Pharmacol. Physiol., 2007 34, 1252–1259 http://dx.doi.org/10.1111/j.1440-1681.2007.04714.x10.1111/j.1440-1681.2007.04714.xSearch in Google Scholar

[15] Al-Majed A.A., Sayed-Ahmed M.M., Al-Yahya A.A., Aleisa A.M., Al-Rejaie S.S., Al-Shabanah O.A., Propionyl-L-carnitine prevents the progression of cisplatin-induced cardiomyopathy in a carnitinedepleted rat model. Pharmacol. Res., 2006 53, 278–286 http://dx.doi.org/10.1016/j.phrs.2005.12.00510.1016/j.phrs.2005.12.005Search in Google Scholar

[16] Sezen O., Ertekin M.V., Demircan B., Karslioglu I., Erdogan F., Kocer I., et al., Vitamin E and L-carnitine, separately or in combination, in the prevention of radiation-induced brain and retinal damages. Neurosurg. Rev., 2008 31, 205–213 http://dx.doi.org/10.1007/s10143-007-0118-010.1007/s10143-007-0118-0Search in Google Scholar

[17] Aydogdu N., Atmaca G., Yalcin O., Taskiran R., Tastekin E., Kaymak K., Protective effects of L-carnitine on myoglobinuric acute renal failure in rats. Clin. Exp. Pharmacol. Physiol., 2006 33, 119–124. http://dx.doi.org/10.1111/j.1440-1681.2006.04336.x10.1111/j.1440-1681.2006.04336.xSearch in Google Scholar

[18] Cetinkaya A., Bulbuloglu E., Kantarceken B., Ciralik H., Kurutas E.B., Buyukbese M.A. et al., Effects of L-carnitine on oxidant/antioxidant status in acetic acid-induced colitis. Dig. Dis. Sci., 2006 51, 488–494 http://dx.doi.org/10.1007/s10620-006-3160-910.1007/s10620-006-3160-9Search in Google Scholar

[19] Ohkawa H., Ohishi N., Yagi K., Assay for lipid peroxidase in animal tissues by thiobarbituric acid reaction. Anal. Biochem., 1979 95, 351–358 http://dx.doi.org/10.1016/0003-2697(79)90738-310.1016/0003-2697(79)90738-3Search in Google Scholar

[20] Tietze F., Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione, applications to mammalian blood and other tissues. Anal. Biochem., 1969 27, 502–522 http://dx.doi.org/10.1016/0003-2697(69)90064-510.1016/0003-2697(69)90064-5Search in Google Scholar

[21] Anderson M.E., Determination of glutathione and glutathione disulfide in biological samples. Methods Enzymol., 1985 113, 548–555 http://dx.doi.org/10.1016/S0076-6879(85)13073-910.1016/S0076-6879(85)13073-9Search in Google Scholar

[22] Paglia D.E., Valentine W.N., Studies on the quantitative and qualitative characterisation of erythrocyte glutathione peroxidase. J. Lab. Clin. Med., 1967 70, 158–69 Search in Google Scholar

[23] Habig W.H., Pabst M.J., Jakoby W.B., Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J. Biol. Chem., 1974 249, 7130–7139 10.1016/S0021-9258(19)42083-8Search in Google Scholar

[24] Sun Y., Oberley L.W., Li Y., A simple method for clinical assay of superoxide dismutase. Clin. Chem., 1988 34, 497–500 10.1093/clinchem/34.3.497Search in Google Scholar

[25] Mohan I.K., Khan M., Shobha J.C., Naidu M.U., Prayag A., Kuppusamy P. et al., Protection against cisplatin-induced nephrotoxicity by Spirulina in rats. Cancer Chemother. Pharmacol., 2006 586, 802–808 http://dx.doi.org/10.1007/s00280-006-0231-810.1007/s00280-006-0231-8Search in Google Scholar PubMed

[26] Sumbuloglu K., Sumbuloglu V., Biyoistatistik. 5th ed. Özdemir Basim Yayim ve Dagitim Ltd. Sti., Ankara, 1996 [in Turkish] Search in Google Scholar

[27] Yilmaz H.R., Sogut S., Ozyurt B., Ozugurlu F., Sahin S., Isik B., et al., The activities of liver adenosine deaminase, xanthine oxidase, catalase, superoxide dismutase enzymes and the levels of malondialdehyde and nitric oxide after cisplatin toxicity in rats: Protective effect of caffeic acid phenethyl ester. Toxicol. Indust. Health., 2005 21, 67–73 http://dx.doi.org/10.1191/0748233705th216oa10.1191/0748233705th216oaSearch in Google Scholar PubMed

[28] Ajith T.A., Nivitha V., Usha S., Zingiber officinale Roscoe alone and in combination with alphatocopherol protect the kidney against cisplatininduced acute renal failure. Food Chem. Toxicol., 2007 45, 921–927 http://dx.doi.org/10.1016/j.fct.2006.11.01410.1016/j.fct.2006.11.014Search in Google Scholar PubMed

[29] Atessahin A., Yilmaz S., Karahan I., Ceribasi A.O., Karaoglu A., Effects of lycopene against cisplatininduced nephrotoxicity and oxidative stres in rats. Toxicology, 2005 212, 116–123 http://dx.doi.org/10.1016/j.tox.2005.04.01610.1016/j.tox.2005.04.016Search in Google Scholar PubMed

[30] Amaral C., Francescato H., Coimbra T., Costa R., Darin J., Antunes L. et al., Resveratrol attenuates cisplatin-induced nephrotoxicity in rats. Arch. Toxicol., 2008 82, 363–370 http://dx.doi.org/10.1007/s00204-007-0262-x10.1007/s00204-007-0262-xSearch in Google Scholar PubMed

[31] Miyamoto Y., Shimada K., Sakaguchi Y., Miyamoto M., Cisplatin (CDDP)-induced acute toxicity in an experimental model of hepatic fibrosis. J. Toxicol. Sci., 2007 32, 311–319 http://dx.doi.org/10.2131/jts.32.31110.2131/jts.32.311Search in Google Scholar PubMed

[32] Sohn J.H., Han K.L., Kim J.H., Rukayadi Y., Hwang J.K., Protective Effects of macelignan on cisplatininduced hepatotoxicity is associated with JNK activation. Biol. Pharm. Bull., 2008 31, 273–277 http://dx.doi.org/10.1248/bpb.31.27310.1248/bpb.31.273Search in Google Scholar PubMed

[33] Tozan A., Sehirli O., Omurtag G.Z., Cetinel S., Gedik N., Sener G., Ginkgo biloba extract reduces naphthalene-induced oxidative damage in mice. Phytother. Res., 2007 21, 72–77 http://dx.doi.org/10.1002/ptr.202710.1002/ptr.2027Search in Google Scholar PubMed

[34] Hanigan M.H., Devarajan P., Cisplatin nephrotoxicity: molecular mechanisms. Cancer Ther., 2003 1, 47–61 Search in Google Scholar

[35] Longoni B., Giovannini L., Migliori M., Bertelli A.A., Bertelli A., Cyclosporine-induced lipid peroxidation and propionyl carnitine protective effect. Int. J. Tissue React., 1999 21, 7–11 Search in Google Scholar

[36] Ferrari R., Merli E., Cicchitelli G., Mele D., Fucili A., Ceconi C., Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: A review. Ann. N.Y. Acad. Sci., 2004 1033, 79–91 http://dx.doi.org/10.1196/annals.1320.00710.1196/annals.1320.007Search in Google Scholar

[37] Sener G., Paskaloglu K., Satiroglu H., Alican I., Kacmaz A., Sakarcan A., L-carnitine ameliorates oxidative damage due to chronic renal failure in rats. J. Cardiovasc. Pharmacol., 2004 43, 698–705 http://dx.doi.org/10.1097/00005344-200405000-0001310.1097/00005344-200405000-00013Search in Google Scholar

[38] Lu Y., Cederbaum A., The mode of cisplatin-induced cell death in CYP2E1-overexpressing HepG2 cells: modulation by ERK, ROS, glutathione, and thioredoxin. Free Radic. Biol. Med., 2007 43, 1061–1075 http://dx.doi.org/10.1016/j.freeradbiomed.2007.06.02110.1016/j.freeradbiomed.2007.06.021Search in Google Scholar

[39] Bompart G., Cisplatin-induced changes in cytochrome P-450, lipid peroxidation and drugmetabolizing enzyme activities in rat kidney cortex. Toxicol. Lett., 1989 48, 193–199 http://dx.doi.org/10.1016/0378-4274(89)90174-410.1016/0378-4274(89)90174-4Search in Google Scholar

[40] Nannelli A., Messina A., Marini S., Trasciatti S., Longo V., Gervasi P.G., Effects of the anticancer dehydrotarplatin on cytochrome P450 and antioxidant enzymes in male rat tissues. Arch. Toxicol., 2007 81, 479–487 http://dx.doi.org/10.1007/s00204-007-0184-710.1007/s00204-007-0184-7Search in Google Scholar PubMed

[41] Arafa H.M., Carnitine deficiency aggravates carboplatin nephropathy through deterioration of energy status, oxidant/anti-oxidant balance, and inflammatory endocoids. Toxicology, 2008 254 (1-2), 51–60 http://dx.doi.org/10.1016/j.tox.2008.09.01010.1016/j.tox.2008.09.010Search in Google Scholar PubMed

[42] Kart A., Yapar K., Karapehlivan M., Citil M., The possible protective effect of L-carnitine on tilmicosin-induced cardiotoxicity in mice. J. Vet. Med. A, 2006 54, 144–146 http://dx.doi.org/10.1111/j.1439-0442.2007.00897.x10.1111/j.1439-0442.2007.00897.xSearch in Google Scholar PubMed

[43] Bianchi G., Vitali G., Caraceni A., Ravaglia S., Capri G., Cundari S., et al., Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl-L-carnitine. Eur. J. Cancer., 2005 41(12), 1746–1750 http://dx.doi.org/10.1016/j.ejca.2005.04.02810.1016/j.ejca.2005.04.028Search in Google Scholar PubMed

[44] Yuce A., Atessahin A., Ceribasi A.O., Aksakal M., Ellagic acid prevents cisplatin-induced oxidative stress in liver and heart tissue of rats. Basic Clin. Pharmacol. Toxicol., 2007 101, 345–349 http://dx.doi.org/10.1111/j.1742-7843.2007.00129.x10.1111/j.1742-7843.2007.00129.xSearch in Google Scholar PubMed

Published Online: 2009-3-27
Published in Print: 2009-6-1

© 2009 Versita Warsaw

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Scroll Up Arrow