Abstract
Background: Chemotherapy with <smlcap>L</smlcap>-asparaginase is associated with hepatotoxicity resulting in organ dysfunction in patients with preexisting liver disorders. This study investigated the protective effect of <smlcap>L</smlcap>-carnitine during chemotherapy in a steatotic rat liver model. Methods: Livers from nonsteatotic and steatotic rats were tested in an isolated liver reperfusion model adding <smlcap>L</smlcap>-asparaginase and <smlcap>L</smlcap>-carnitine to the reperfusate. Portal venous pressure (PVP), hepatic oxygen consumption, aspartate aminotransferase, lactate dehydrogenase, glutamate dehydrogenase and α-glutathione S-transferase levels were assessed. Further histopathological analysis was performed and cytotoxicity was verified in vitro. Results:<smlcap>L</smlcap>-Asparaginase induced toxicity in fatty livers whereas low toxicity was observed in normal livers. <smlcap>L</smlcap>-Carnitine induced a decline in PVP and oxygen consumption, and reduced parenchymal and mitochondrial damage in fatty livers. Cytotoxicity of <smlcap>L</smlcap>-asparaginase was not impaired by the presence of <smlcap>L</smlcap>-carnitine. Conclusions: Our study emphasizes the potential of <smlcap>L</smlcap>-carnitine to reduce <smlcap>L</smlcap>-asparaginase-induced hepatotoxicity in patients with preexisting liver disorders.
Journal Section:
Editor's choice
Keywords:
<span style="font-variant:small-caps; text-transform:lowercase">L</span>-Asparaginase,
<span style="font-variant:small-caps; text-transform:lowercase">L</span>-Carnitine,
Chemotherapy,
Leukemia,
Liver toxicity,
Lymphoma,
Rat model of liver reperfusion,
Steatotic liver
References
1.
Avramis VI, Tiwari PN: Asparaginase (native ASNase or pegylated ASNase) in the treatment of acute lymphoblastic leukemia. Int J Nanomedicine 2006;1:241-254.
[PubMed]
2.
Pieters R, Hunger SP, Boos J, Rizzari C, Silverman L, Baruchel A, Goekbuget N, Schrappe M, Pui CH: L-Asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase. Cancer 2011;117:238-249.
[PubMed]
3.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011;61:69-90.
[PubMed]
4.
Earl M: Incidence and management of asparaginase-associated adverse events in patients with acute lymphoblastic leukemia. Clin Adv Hematol Oncol 2009;7:600-606.
[PubMed]
5.
Avramis VI, Panosyan EH: Pharmacokinetic/pharmacodynamic relationships of asparaginase formulations: the past, the present and recommendations for the future. Clin Pharmacokinet 2005;44:367-393.
[PubMed]
6.
Narta UK, Kanwar SS, Azmi W: Pharmacological and clinical evaluation of L-asparaginase in the treatment of leukemia. Crit Rev Oncol Hematol 2007;61:208-221.
[PubMed]
7.
Muller HJ, Boos J: Use of L-asparaginase in childhood ALL. Crit Rev Oncol Hematol 1998;28:97-113.
[PubMed]
8.
Jenkins R, Perlin E: Severe hepatotoxicity from Escherichia coli L-asparaginase. J Natl Med Assoc 1987;79:775-779.
[PubMed]
9.
Torres DM, Williams CD, Harrison SA: Features, diagnosis, and treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2012;10:837-858.
[PubMed]
10.
Miki C, Iriyama K, Mirza DF, Mayer AD, Buckels JA, Suzuki H, McMaster P: Postperfusion energy metabolism of steatotic graft and its relation to early graft viability following liver transplantation. Dig Dis Sci 1998;43:74-79.
[PubMed]
11.
Mori T, Sugita K, Suzuki T, Ishikawa T, Kurosawa H, Matsui A: Histopathologic features of the biopsied liver at onset of childhood B-precursor acute lymphoblastic leukemia presenting as severe jaundice. J Pediatr Gastroenterol Nutr 1997;25:354-357.
[PubMed]
12.
Soh LT, Ang PT, Sng I, Chua EJ, Ong YW: Fulminant hepatic failure in non-Hodgkin lymphoma patients treated with chemotherapy. Eur J Cancer 1992;28A:1338-1339.
[PubMed]
13.
Bodmer M, Sulz M, Stadlmann S, Droll A, Terracciano L, Krahenbuhl S: Fatal liver failure in an adult patient with acute lymphoblastic leukemia following treatment with L-asparaginase. Digestion 2006;74:28-32.
[PubMed]
14.
Bessho F, Kinumaki H, Yokota S, Hayashi Y, Kobayashi M, Kamoshita S: Liver function studies in children with acute lymphocytic leukemia after cessation of therapy. Med Pediatr Oncol 1994;23:111-115.
[PubMed]
15.
Cairo MS: Adverse reactions of L-asparaginase. Am J Pediatr Hematol Oncol 1982;4:335-339.
[PubMed]
16.
Parsons SK, Skapek SX, Neufeld EJ, Kuhlman C, Young ML, Donnelly M, Brunzell JD, Otvos JD, Sallan SE, Rifai N: Asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia. Blood 1997;89:1886-1895.
[PubMed]
17.
Celle G, Dodero M, Pannacciulli I: The liver damaging effect of L-asparaginase - an experimental study of chronic toxicity. Eur J Cancer 1973;9:55-57.
[PubMed]
18.
Durden DL, Salazar AM, Distasio JA: Kinetic analysis of hepatotoxicity associated with antineoplastic asparaginases. Cancer Res 1983;43:1602-1605.
[PubMed]
19.
Pratt CB, Johnson WW: Duration and severity of fatty metamorphosis of the liver following L-asparaginase therapy. Cancer 1971;28:361-364.
[PubMed]
20.
Sahoo S, Hart J: Histopathological features of L-asparaginase-induced liver disease. Semin Liver Dis 2003;23:295-299.
[PubMed]
21.
Goekbuget N, Baumann A, Beck J, Boos J, Brueggemann M, Diedrich H, et al: PEG-asparaginase in adult acute lymphoblastic leukemia (ALL): efficacy and feasibility analysis with increasing dose levels (abstract). Blood 2008;112:302.
22.
Bremer J: Carnitine - metabolism and functions. Physiol Rev 1983;63:1420-1480.
[PubMed]
23.
Bahl JJ, Bressler R: The pharmacology of carnitine. Annu Rev Pharmacol Toxicol 1987;27:257-277.
[PubMed]
24.
Malaguarnera M, Gargante MP, Russo C, Antic T, Vacante M, Malaguarnera M, Avitabile T, Li VG, Galvano F: L-Carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis - a randomized and controlled clinical trial. Am J Gastroenterol 2010;105:1338-1345.
[PubMed]
25.
Chang B, Nishikawa M, Nishiguchi S, Inoue M: L-Carnitine inhibits hepatocarcinogenesis via protection of mitochondria. Int J Cancer 2005;113:719-729.
[PubMed]
26.
Socha P, Horvath A, Vajro P, Dziechciarz P, Dhawan A, Szajewska H: Pharmacological interventions for nonalcoholic fatty liver disease in adults and in children: a systematic review. J Pediatr Gastroenterol Nutr 2009;48:587-596.
[PubMed]
27.
Tufekci O, Gunes D, Ozogul C, Kolatan E, Altun Z, Yilmaz O, Aktas S, Erbayraktar Z, Kirkim G, Mutafoglu K, Soylu A, Serbetcioglu B, Guneri EA, Olgun N: Evaluation of the effect of acetyl L-carnitine on experimental cisplatin nephrotoxicity. Chemotherapy 2009;55:451-459.
[PubMed]
28.
Alshabanah OA, Hafez MM, Al-Harbi MM, Hassan ZK, Al Rejaie SS, Asiri YA, Sayed-Ahmed MM: Doxorubicin toxicity can be ameliorated during antioxidant L-carnitine supplementation. Oxid Med Cell Longev 2010;3:428-433.
[PubMed]
29.
Tolba RH, Putz U, Decker D, Dombrowski F, Lauschke H: L-Carnitine ameliorates abnormal vulnerability of steatotic rat livers to cold ischemic preservation. Transplantation 2003;76:1681-1686.
[PubMed]
30.
Delzenne NM, Hernaux NA, Taper HS: A new model of acute liver steatosis induced in rats by fasting followed by refeeding a high carbohydrate-fat free diet. Biochemical and morphological analysis. J Hepatol 1997;26:880-885.
[PubMed]
31.
Minor T, Akbar S, Tolba R: Value of alpha glutathione S-transferase for in vitro evaluation of preservation injury in normal and steatotic livers. Transpl Int 2000;13(suppl 1):S551-S554.
[PubMed]
32.
Ludwig J, McGill DB, Lindor KD: Review: nonalcoholic steatohepatitis. J Gastroenterol Hepatol 1997;12:398-403.
[PubMed]
33.
Clark JM, Diehl AM: Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA 2003;289:3000-3004.
[PubMed]
34.
Broome JD: Evidence that the L-asparaginase of guinea pig serum is responsible for its antilymphoma effects. I. Properties of the L-asparaginase of guinea pig serum in relation to those of the antilymphoma substance. J Exp Med 1963;118:99-120.
[PubMed]
35.
Villa P, Corada M, Bartosek I: L-asparaginase effects on inhibition of protein synthesis and lowering of the glutamine content in cultured rat hepatocytes. Toxicol Lett 1986;32:235-241.
[PubMed]
36.
Haskell CM, Canellos GP, Leventhal BG, Carbone PP, Serpick AA, Hansen HH: L-Asparaginase toxicity. Cancer Res 1969;29:974-975.
[PubMed]
37.
Haskell CM: L-Asparaginase: human toxicology and single agent activity in nonleukemic neoplasms. Cancer Treat Rep 1981;65(suppl 4):57-59.
[PubMed]
38.
Al-Majed AA: Carnitine deficiency provokes cisplatin-induced hepatotoxicity in rats. Basic Clin Pharmacol Toxicol 2007;100:145-150.
[PubMed]
39.
Fukumori T, Ohkohchi N, Tsukamoto S, Satomi S: The mechanism of injury in a steatotic liver graft during cold preservation. Transplantation 1999;67:195-200.
[PubMed]
40.
Takahashi K, Hakamada K, Totsuka E, Umehara Y, Sasaki M: Warm ischemia and reperfusion injury in diet-induced canine fatty livers. Transplantation 2000;69:2028-2034.
[PubMed]
41.
Sun CK, Zhang XY, Zimmermann A, Davis G, Wheatley AM: Effect of ischemia-reperfusion injury on the microcirculation of the steatotic liver of the Zucker rat. Transplantation 2001;72:1625-1631.
[PubMed]
42.
Ijaz S, Yang W, Winslet MC, Seifalian AM: Impairment of hepatic microcirculation in fatty liver (review). Microcirculation 2003;10:447-456.
[PubMed]
43.
Li JL, Wang QY, Luan HY, Kang ZC, Wang CB: Effects of L-carnitine against oxidative stress in human hepatocytes: involvement of peroxisome proliferator-activated receptor alpha. J Biomed Sci 2012;19:32.
[PubMed]
44.
Aleisa AM, Al-Majed AA, Al-Yahya AA, Al-Rejaie SS, Bakheet SA, Al-Shabanah OA, Sayed-Ahmed MM: 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.
[PubMed]
45.
Gunes D, Kirkim G, Kolatan E, Guneri EA, Ozogul C, Altun Z, Serbetcioglu B, Yilmaz O, Aktas S, Mutafoglu K, Tufekci O, Erbayraktar Z, Olgun N: Evaluation of the effect of acetyl L-carnitine on experimental cisplatin ototoxicity and neurotoxicity. Chemotherapy 2011;57:186-194.
[PubMed]
46.
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 Physiol Pathol Clin Med 2007;54:144-146.
[PubMed]
47.
Andrieu-Abadie N, Jaffrezou JP, Hatem S, Laurent G, Levade T, Mercadier JJ: L-Carnitine prevents doxorubicin-induced apoptosis of cardiac myocytes: role of inhibition of ceramide generation. FASEB J 1999;13:1501-1510.
[PubMed]
48.
Niang M, Soukup T, Zivny P, Tomsik P, Bukac J, Rezacova M, Stoklasova A, Cerman J, Sispera L: Biochemical and pharmacological effects of mitoxantrone and acetyl-L-carnitine in mice with a solid form of Ehrlich tumour. Chemotherapy 2011;57:35-42.
[PubMed]
49.
Pande SV, Parvin R: Carnitine-acylcarnitine translocase catalyzes an equilibrating unidirectional transport as well. J Biol Chem 1980;255:2994-3001.
[PubMed]
50.
Battelli D, Bellei M, Arrigoni-Martelli E, Muscatello U, Bobyleva V: Interaction of carnitine with mitochondrial cardiolipin. Biochim Biophys Acta 1992;1117:33-36.
[PubMed]
51.
Loster H, Punzel M: Effects of L-carnitine on mechanical recovery of isolated rat hearts in relation to the perfusion with glucose and palmitate. Mol Cell Biochem 1998;185:65-75.
[PubMed]
52.
Di GC, Latteri F, Fichera C, Sorrenti V, Campisi A, Castorina C, Russo A, Pinturo R, Vanella A: Effect of acetyl-L-carnitine on lipid peroxidation and xanthine oxidase activity in rat skeletal muscle. Neurochem Res 1993;18:1157-1162.
[PubMed]
© 2013 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2013
You do not currently have access to this content.
