Protective Effect of L-Carnitine against Gentamicin-Induced Nephrotoxicity in Rats
This study aimed to determine the possible protective effects of L‐carnitine against gentamicin‐induced nephrotoxicity. Forty male albino rats were divided into 4 groups (10 rats each); Group 1: normal control, group 2: induced nephrotoxicity (gentamicin 50 mg/kg/day S.C; 8 days), group 3: treated with L‐ carnitine (40 mg/kg/d SC for 12 days) and group 4: treated with L‐ carnitine 4 days before and for 8 days in concomitant with gentamicin. Gentamicin‐induced nephrotoxicity (group 2): caused significant increase in serum urea, creatinine, urinary N‐acetyl‐B‐D‐ glucosaminidase (NAG), gamma glutamyl transpeptidase (GGT), urinary total protein and kidney tissue malondialdehyde (MDA) with significant decrease in serum superoxide dismutase (SOD), serum catalase and creatinine clearance and marked tubular necrosis in the proximal convoluted tubules with interruption in the basement membrane around the necrotic tubule compared to the normal control group. L‐carnitine 4 days before and for 8 days in concomitant with gentamicin (group 4) offered marked decrease in serum urea, serum creatinine, urinary NAG, urinary GGT, urinary proteins and kidney tissue MDA, with marked increase in serum SOD, serum catalase and creatinine clearance with marked improvement in the tubular damage compared to gentamicin‐induced nephrotoxicity group. L‐carnitine administered for 12 days produced no change in the parameters mentioned above as compared to the normal control group. In conclusion: L‐carnitine could reduce most of the biochemical parameters and also improve the histopathological features of kidney asscociated with gentamicin induced‐nephrotoxicity.
[1] Abdel-aleem S, Nada MA, Sayed-Ahmed M, Hendrickson SC, St Louis
J, Walthall HP, Lowe JE. (1996): Regulation of fatty acid oxidation by
acetyl-CoA generated from glucose utilization in isolated myocytes. J
Mol Cell Cardiol. ; 28(5):825-33.
[2] Al-Shabanah OA, Aleisa AM, Al-Yahya AA, Al-Rejaie SS, Bakheet
SA, Fatani AG, Sayed-Ahmed MM. (2010): Increased urinary losses of
carnitine and decreased intramitochondrial coenzyme A in gentamicininduced
acute renal failure in rats. Nephrol. Dial. Transplant..; 25(1):69-
76.
[3] Arduini A, Rossi M, Mancinelli O, et al. (1990): Effect of L-carnitine
and acetyl L-carnitine on the human erythrocyte membrane stability and
deformability. Life Sci; 47:2395–400.
[4] Bartels H., Boehmer M. (1971): Micro-determination of creatinine. Clin.
Chim. Acta. ; 32:81–85.
[5] Begg EJ, Barclay ML, Kirkpatrick CM. (2001): The therapeutic
monitoring of antimicrobial agents.Br J Clin Pharmacol. 52:35S–43S.
[6] Bennett WM, Mela-Riker LM, Houghton DC, Gilbert DN, Buss WC.
(1988): Microsomal protein synthesis inhibition: an early manifestation
of gentamicin nephrotoxicity. Am J Physiol.; 255: F265-9.
[7] Bremer J. (1983): Carnitine--metabolism and functions. Physiol Rev.;
63(4):1420-80.
[8] Clairborne, A. (2000): Catalase acivity. In: Greenwald, E.R. (Ed.).
Handbook of Methods for Oxygen Radical Research, CRC Press,
Florida, pp: 283-284.
[9] Cockcroft DW, Gault MH. (1976): Prediction of creatinine clearance
from serum creatinine. Nephron. ; 16(1):31-41.
[10] De la Cruz Rodríguez, Carmen Rosa Araujo, Sara Emilia Posleman,
María Rosario Rey (2010): Attenuation of gentamicin-induced
nephrotoxicity: trimetazidine versus N-acetyl cysteine. J. Apple.
Toxicol. 30(4):343-53.
[11] Erdem, A., Gundogan, N.U., Usubutun, A., Kilinc, K., Erdem, S.R.,
Kara, A., Bozkurt, A. (2000): The protective effect of taurine against
gentamicin-induced acute tubular necrosis in rats. Nephrol.
Dial.Transplant. 15, 1175–1182.
[12] Ergün O, Ulman C, Kiliçalp AS, Ulman I. (2001): Carnitine as a
preventive agent in experimental renal ischemia-reperfusion injury. Urol
Res.; 29(3):186-9.
[13] Fawcett JK and Scott JE (1960): A rapid and precise method for the
determination of urea. Clin Pathol.; 13:156-9.
[14] Giovannini L, Migliori M, De Pietro S, Taccola D, Panichi V, Bertelli
AA, Bertelli A. (1999): L-propionyl carnitine reduces toxicity correlated
to cyclosporine-induced intracellular ATP concentrations. Drugs Exp
Clin Res.; 25(4):173-7.
[15] Halliwell B, Chirico S. (1993): Lipid peroxidation: its mechanism,
measurement and significance. Am J Clin Nutr. 57:715–25.
[16] Haywood, J.P.; Shaffer, R.A. and Fastenow, C. (1981): Regional blood
flow measurment with plused Doppler flowmeter in conscious rats. Am.
J. Physiol., 241: 273-78.
[17] Kaloyanides GJ, Ramsammy L S. (1991): Alterations of biophysical
properties of liposomes predict aminoglycoside toxicity: inhibitory
effect of polyaspartic acid. In: Bach PH, Delacrey L, Gregg NJ, Wilks
MF, eds. Proceedings of the Fourth International Symposium on
Nephrotoxicity. Marcel Dekker, New York; 117–126.
[18] Kaloyanides, G. J. (1984): Aminoglycoside-Induced Functional and
Biochemical Defects in the Renal Cortex. Fundam. Appl. Toxicol. ;
930–943.
[19] Kirschbaum BB. (1984): Interactions between renal brush border
membranes and polyamines. J Pharmacol Exp Ther ; 229(2):409-16.
[20] Klein G, Geibel E. (1990): Evaluation of a new photometric assay for
the kinetic determination of N-acetyl-b-D-glucosaminidase in urine
samples. Progr Med Lab; 4/5: 450.
[21] Kopple JD, Ding H, Letoha A, Ivanyi B,Qing DP, Dux L. (2002): lCarnitine
ameliorates gentamicin-induced renal injury in rats. Nephrol
Dial Transplant.17:2122–31.
[22] Longoni B, Giovannini L, Migliori M, Bertelli AA, Bertelli A. ( 1999):
Cyclosporine-induced lipid peroxidation and propionyl carnitine
protective effect. Int J Tissue React. ; 21(1):7-11.
[23] Misra, HP. (2000): Adrenochrome assay. In Greenwald, A.R. (Ed.).
Hand books of Methods for Oxygen Radical Research. CRC Press,
Florida, pp: 237-242.
[24] Moriyama T, Nakahama H, Fukuhara Y, Horio M, Yanase M, Orita Y,
Kamada T, Kanashiro M, Miyake Y. (1989): Decrease in the fluidity of
brush-border membrane vesicles induced by gentamicin. A spin labeling
study. Biochem Pharmacol. ; 38(7):1169-74.
[25] Moudden M, Laurent G, Leclercq M, Tulkens P. (2000): Gentamicin
induced apoptosis in renal cell lines and embryonic rat fibroblasts.
Toxicol Sci. 56:229–39.
[26] Mouedden M., Laurent G. and Tulkens PM. (2010): Mechanism of
Protective Effect of L-carnitine on Human Kidney Tubular Epithelial
Cell Line Injury Induced by Oxidative Stress, Posted on May, 17, 2010
by China Papers.
[27] Orsonneau JL, Douet P, Massoubre C, Lustenberger P, Bernard S.
(1989) :An improved Pyrogallol Red-Molybdate Method for
Determining Total Urinary Protein. Clin Chem.; 35:2233-6.
[28] Packer L, Valenza M, Serbinova E, Starke-Reed P, Frost K, Kagan V.
(1991): Free radical scavenging is involved in the protective effect of Lpropionyl-carnitine
against ischemia-reperfusion injury of the heart.
Arch Biochem Biophys. ; 288(2):533-7.
[29] Parlakpinar H, Tasdemir S, Polat A, Bay-Karabulut A, Vardi N, Ucar M.
(2006): Protective effect of chelerythrine on gentamicin-induced
nephrotoxicity. Cell Biochem Funct. 24(1):41–8.
[30] Parlakpinar, H., Ozer,M.K., Sahna, E., Vardi, N., Cigremis, Y., Acet, A.
(2003): Amikacin-induced acute renal injury in rats: protective role of
melatonin. J. Pineal. Res. 35, 85–90.
[31] Pedraza-Chaverrí J, Gonzalez-Orozcoa AE, Maldonado PD, Barrera D,
Medina-Campos ON, Hernandez-Pando R. (2003): Diallyl disulfide
ameliorates gentamicin induced oxidative stress and nephropathy in rats.
Eur J Pharmacol. 473: 71–8.
[32] Pedraza-Chaverri, J., Maldonado, P.D., Mediana-Campos, O.N.,
Olivares-Corichi, I.M., Granados-Silvestre, M.A., Hernandez- Pando, R
Ibarra-Rubio, M.E. (2000): Garlic ameliorates gentam icin
nephrotoxicity: relation to antioxidant enzymes. Free Radic. Biol. Med.
29, 602–611.
[33] Prins JM, Weverling GJ, de Blok K, van Ketel RJ, Speelman P. (1996):
Validation and nephrotoxicity of a simplified once-daily aminoglycoside
dosing schedule and guidelines for monitoring therapy. Anti-microb
Agents Chemother. 40: 2494–9.
[34] Ramsammy LS, Kaloyanides GJ. (1987): Effect of gentamicin on the
transition temperature and permeability to glycerol of
phosphatidylinositol-containing liposomes. Biochem Pharmacol;
36(7):1179-81.
[35] Reiter, R.J., Tan, D., Sainz, R.M., Mayo, J.C., Lopez, B.S. (2002):
Melatonin reducing the toxicity and increasing the efficacy of drugs. J.
Pharm. Pharmacol. 5, 1299–1321.
[36] Sandoval RM, Dunn KW, Molitoris BA. (2000): Gentamicin traffics
rapidly and directly to the Golgi complex in LLC-PK (1) cells. Am J
Physiol Renal Physiol.; 279(5):F884-90.
[37] Selby NM, Shaw SM, Woodier N, Fluck RJ, Kohle NV. (2009):
Gentamicin-associated acute kidney injury. Q J Med.102:873–80.
[38] Shug AL. (1987): Protection from adriamycin-induced cardiomyopathy
in rats. Z, Kardiol. ; 76 Suppl 5:46-52.
[39] Steiber A, Kerner J, Hoppel CL. (2004): Carnitine: a nutritional,
biosynthetic, and functional perspective. Mol Aspects Med.; 25(5-
6):455-73.
[40] Sweileh WM. (2009): A prospective comparative study of gentamicinand
amikacininduced nephrotoxicity in patients with normal baseline
renal function. Fundam Clin Pharmacol. 23(4):515–20.
[41] Szasz, G. (1969): A kinetic photometric method for serum γglutamyl
transpeptidase.Clin. Chem. 15: 124–136.
[42] Walker PD and Shah SV (1988): Evidence Suggesting a Role for
Hydroxyl Radical in Gentamicin-induced acute renal failure in Rats. J.
Clin. Invest. ; 81: 334-341.
[43] Walker PD, Barri Y, Shah SV. (1999): Oxidant mechanisms in
gentamicin nephrotoxicity. Ren Fail.; 21(3-4):433-42.
[44] Weinberg JM, Humes HD (1980): Mechanisms of gentamicin-induced
dysfunction of renal cortical mitochondria. I. Effects of mitochondrial
respiration. Arch Biochem Biophys; 205:222–231.
[45] Williams PD, Holohan PD, and Ross CR (1981): Gentamicin
nephrotoxicity. II. Plasma membrane changes. Toxicol, Appl.
Pharmacol.61:243–251.
[1] Abdel-aleem S, Nada MA, Sayed-Ahmed M, Hendrickson SC, St Louis
J, Walthall HP, Lowe JE. (1996): Regulation of fatty acid oxidation by
acetyl-CoA generated from glucose utilization in isolated myocytes. J
Mol Cell Cardiol. ; 28(5):825-33.
[2] Al-Shabanah OA, Aleisa AM, Al-Yahya AA, Al-Rejaie SS, Bakheet
SA, Fatani AG, Sayed-Ahmed MM. (2010): Increased urinary losses of
carnitine and decreased intramitochondrial coenzyme A in gentamicininduced
acute renal failure in rats. Nephrol. Dial. Transplant..; 25(1):69-
76.
[3] Arduini A, Rossi M, Mancinelli O, et al. (1990): Effect of L-carnitine
and acetyl L-carnitine on the human erythrocyte membrane stability and
deformability. Life Sci; 47:2395–400.
[4] Bartels H., Boehmer M. (1971): Micro-determination of creatinine. Clin.
Chim. Acta. ; 32:81–85.
[5] Begg EJ, Barclay ML, Kirkpatrick CM. (2001): The therapeutic
monitoring of antimicrobial agents.Br J Clin Pharmacol. 52:35S–43S.
[6] Bennett WM, Mela-Riker LM, Houghton DC, Gilbert DN, Buss WC.
(1988): Microsomal protein synthesis inhibition: an early manifestation
of gentamicin nephrotoxicity. Am J Physiol.; 255: F265-9.
[7] Bremer J. (1983): Carnitine--metabolism and functions. Physiol Rev.;
63(4):1420-80.
[8] Clairborne, A. (2000): Catalase acivity. In: Greenwald, E.R. (Ed.).
Handbook of Methods for Oxygen Radical Research, CRC Press,
Florida, pp: 283-284.
[9] Cockcroft DW, Gault MH. (1976): Prediction of creatinine clearance
from serum creatinine. Nephron. ; 16(1):31-41.
[10] De la Cruz Rodríguez, Carmen Rosa Araujo, Sara Emilia Posleman,
María Rosario Rey (2010): Attenuation of gentamicin-induced
nephrotoxicity: trimetazidine versus N-acetyl cysteine. J. Apple.
Toxicol. 30(4):343-53.
[11] Erdem, A., Gundogan, N.U., Usubutun, A., Kilinc, K., Erdem, S.R.,
Kara, A., Bozkurt, A. (2000): The protective effect of taurine against
gentamicin-induced acute tubular necrosis in rats. Nephrol.
Dial.Transplant. 15, 1175–1182.
[12] Ergün O, Ulman C, Kiliçalp AS, Ulman I. (2001): Carnitine as a
preventive agent in experimental renal ischemia-reperfusion injury. Urol
Res.; 29(3):186-9.
[13] Fawcett JK and Scott JE (1960): A rapid and precise method for the
determination of urea. Clin Pathol.; 13:156-9.
[14] Giovannini L, Migliori M, De Pietro S, Taccola D, Panichi V, Bertelli
AA, Bertelli A. (1999): L-propionyl carnitine reduces toxicity correlated
to cyclosporine-induced intracellular ATP concentrations. Drugs Exp
Clin Res.; 25(4):173-7.
[15] Halliwell B, Chirico S. (1993): Lipid peroxidation: its mechanism,
measurement and significance. Am J Clin Nutr. 57:715–25.
[16] Haywood, J.P.; Shaffer, R.A. and Fastenow, C. (1981): Regional blood
flow measurment with plused Doppler flowmeter in conscious rats. Am.
J. Physiol., 241: 273-78.
[17] Kaloyanides GJ, Ramsammy L S. (1991): Alterations of biophysical
properties of liposomes predict aminoglycoside toxicity: inhibitory
effect of polyaspartic acid. In: Bach PH, Delacrey L, Gregg NJ, Wilks
MF, eds. Proceedings of the Fourth International Symposium on
Nephrotoxicity. Marcel Dekker, New York; 117–126.
[18] Kaloyanides, G. J. (1984): Aminoglycoside-Induced Functional and
Biochemical Defects in the Renal Cortex. Fundam. Appl. Toxicol. ;
930–943.
[19] Kirschbaum BB. (1984): Interactions between renal brush border
membranes and polyamines. J Pharmacol Exp Ther ; 229(2):409-16.
[20] Klein G, Geibel E. (1990): Evaluation of a new photometric assay for
the kinetic determination of N-acetyl-b-D-glucosaminidase in urine
samples. Progr Med Lab; 4/5: 450.
[21] Kopple JD, Ding H, Letoha A, Ivanyi B,Qing DP, Dux L. (2002): lCarnitine
ameliorates gentamicin-induced renal injury in rats. Nephrol
Dial Transplant.17:2122–31.
[22] Longoni B, Giovannini L, Migliori M, Bertelli AA, Bertelli A. ( 1999):
Cyclosporine-induced lipid peroxidation and propionyl carnitine
protective effect. Int J Tissue React. ; 21(1):7-11.
[23] Misra, HP. (2000): Adrenochrome assay. In Greenwald, A.R. (Ed.).
Hand books of Methods for Oxygen Radical Research. CRC Press,
Florida, pp: 237-242.
[24] Moriyama T, Nakahama H, Fukuhara Y, Horio M, Yanase M, Orita Y,
Kamada T, Kanashiro M, Miyake Y. (1989): Decrease in the fluidity of
brush-border membrane vesicles induced by gentamicin. A spin labeling
study. Biochem Pharmacol. ; 38(7):1169-74.
[25] Moudden M, Laurent G, Leclercq M, Tulkens P. (2000): Gentamicin
induced apoptosis in renal cell lines and embryonic rat fibroblasts.
Toxicol Sci. 56:229–39.
[26] Mouedden M., Laurent G. and Tulkens PM. (2010): Mechanism of
Protective Effect of L-carnitine on Human Kidney Tubular Epithelial
Cell Line Injury Induced by Oxidative Stress, Posted on May, 17, 2010
by China Papers.
[27] Orsonneau JL, Douet P, Massoubre C, Lustenberger P, Bernard S.
(1989) :An improved Pyrogallol Red-Molybdate Method for
Determining Total Urinary Protein. Clin Chem.; 35:2233-6.
[28] Packer L, Valenza M, Serbinova E, Starke-Reed P, Frost K, Kagan V.
(1991): Free radical scavenging is involved in the protective effect of Lpropionyl-carnitine
against ischemia-reperfusion injury of the heart.
Arch Biochem Biophys. ; 288(2):533-7.
[29] Parlakpinar H, Tasdemir S, Polat A, Bay-Karabulut A, Vardi N, Ucar M.
(2006): Protective effect of chelerythrine on gentamicin-induced
nephrotoxicity. Cell Biochem Funct. 24(1):41–8.
[30] Parlakpinar, H., Ozer,M.K., Sahna, E., Vardi, N., Cigremis, Y., Acet, A.
(2003): Amikacin-induced acute renal injury in rats: protective role of
melatonin. J. Pineal. Res. 35, 85–90.
[31] Pedraza-Chaverrí J, Gonzalez-Orozcoa AE, Maldonado PD, Barrera D,
Medina-Campos ON, Hernandez-Pando R. (2003): Diallyl disulfide
ameliorates gentamicin induced oxidative stress and nephropathy in rats.
Eur J Pharmacol. 473: 71–8.
[32] Pedraza-Chaverri, J., Maldonado, P.D., Mediana-Campos, O.N.,
Olivares-Corichi, I.M., Granados-Silvestre, M.A., Hernandez- Pando, R
Ibarra-Rubio, M.E. (2000): Garlic ameliorates gentam icin
nephrotoxicity: relation to antioxidant enzymes. Free Radic. Biol. Med.
29, 602–611.
[33] Prins JM, Weverling GJ, de Blok K, van Ketel RJ, Speelman P. (1996):
Validation and nephrotoxicity of a simplified once-daily aminoglycoside
dosing schedule and guidelines for monitoring therapy. Anti-microb
Agents Chemother. 40: 2494–9.
[34] Ramsammy LS, Kaloyanides GJ. (1987): Effect of gentamicin on the
transition temperature and permeability to glycerol of
phosphatidylinositol-containing liposomes. Biochem Pharmacol;
36(7):1179-81.
[35] Reiter, R.J., Tan, D., Sainz, R.M., Mayo, J.C., Lopez, B.S. (2002):
Melatonin reducing the toxicity and increasing the efficacy of drugs. J.
Pharm. Pharmacol. 5, 1299–1321.
[36] Sandoval RM, Dunn KW, Molitoris BA. (2000): Gentamicin traffics
rapidly and directly to the Golgi complex in LLC-PK (1) cells. Am J
Physiol Renal Physiol.; 279(5):F884-90.
[37] Selby NM, Shaw SM, Woodier N, Fluck RJ, Kohle NV. (2009):
Gentamicin-associated acute kidney injury. Q J Med.102:873–80.
[38] Shug AL. (1987): Protection from adriamycin-induced cardiomyopathy
in rats. Z, Kardiol. ; 76 Suppl 5:46-52.
[39] Steiber A, Kerner J, Hoppel CL. (2004): Carnitine: a nutritional,
biosynthetic, and functional perspective. Mol Aspects Med.; 25(5-
6):455-73.
[40] Sweileh WM. (2009): A prospective comparative study of gentamicinand
amikacininduced nephrotoxicity in patients with normal baseline
renal function. Fundam Clin Pharmacol. 23(4):515–20.
[41] Szasz, G. (1969): A kinetic photometric method for serum γglutamyl
transpeptidase.Clin. Chem. 15: 124–136.
[42] Walker PD and Shah SV (1988): Evidence Suggesting a Role for
Hydroxyl Radical in Gentamicin-induced acute renal failure in Rats. J.
Clin. Invest. ; 81: 334-341.
[43] Walker PD, Barri Y, Shah SV. (1999): Oxidant mechanisms in
gentamicin nephrotoxicity. Ren Fail.; 21(3-4):433-42.
[44] Weinberg JM, Humes HD (1980): Mechanisms of gentamicin-induced
dysfunction of renal cortical mitochondria. I. Effects of mitochondrial
respiration. Arch Biochem Biophys; 205:222–231.
[45] Williams PD, Holohan PD, and Ross CR (1981): Gentamicin
nephrotoxicity. II. Plasma membrane changes. Toxicol, Appl.
Pharmacol.61:243–251.
@article{"International Journal of Medical, Medicine and Health Sciences:70335", author = "Mohamed F. Ahmed and Mabruka S. Elashheb and Fatma M. Ben Rabha", title = "Protective Effect of L-Carnitine against Gentamicin-Induced Nephrotoxicity in Rats", abstract = "This study aimed to determine the possible protective effects of L‐carnitine against gentamicin‐induced nephrotoxicity. Forty male albino rats were divided into 4 groups (10 rats each); Group 1: normal control, group 2: induced nephrotoxicity (gentamicin 50 mg/kg/day S.C; 8 days), group 3: treated with L‐ carnitine (40 mg/kg/d SC for 12 days) and group 4: treated with L‐ carnitine 4 days before and for 8 days in concomitant with gentamicin. Gentamicin‐induced nephrotoxicity (group 2): caused significant increase in serum urea, creatinine, urinary N‐acetyl‐B‐D‐ glucosaminidase (NAG), gamma glutamyl transpeptidase (GGT), urinary total protein and kidney tissue malondialdehyde (MDA) with significant decrease in serum superoxide dismutase (SOD), serum catalase and creatinine clearance and marked tubular necrosis in the proximal convoluted tubules with interruption in the basement membrane around the necrotic tubule compared to the normal control group. L‐carnitine 4 days before and for 8 days in concomitant with gentamicin (group 4) offered marked decrease in serum urea, serum creatinine, urinary NAG, urinary GGT, urinary proteins and kidney tissue MDA, with marked increase in serum SOD, serum catalase and creatinine clearance with marked improvement in the tubular damage compared to gentamicin‐induced nephrotoxicity group. L‐carnitine administered for 12 days produced no change in the parameters mentioned above as compared to the normal control group. In conclusion: L‐carnitine could reduce most of the biochemical parameters and also improve the histopathological features of kidney asscociated with gentamicin induced‐nephrotoxicity.
", keywords = "Gentamicin, kidney disease, L‐carnitine,
nephrotoxicity.", volume = "7", number = "11", pages = "767-6", }
