Abstract
Cyclosporine A (CsA) is a potent immunosuppressor that is widely used in transplant surgery and the treatment of several autoimmune diseases. However, major side effects of CsA such as nephrotoxicity, hepatotox-icity, neurotoxicity and cardiovascular diseases have substantially limited its usage. Although molecular mechanisms underlying these adverse effects are not clearly understood, there is some evidence that suggests involvement of reactive oxygen species (ROS). In parallel, protective effects of various antioxidants have been demonstrated by many research groups. Extensive studies of CsA-induced nephrotoxcity have confirmed that the antioxidants can restore the damaged function and structure of kidney. Subsequently, there have appeared numerous reports to demonstrate the positive antioxidant effects on liver and other organ damages by CsA. It may be timely to review the ideas to envisage the relationship between ROS and the CsA-induced toxicity. This review is comprised of a brief description of the immunosuppressive action and the secondary effects of CsA, and a synopsis of reports regarding the antioxidant treatments against the ROS-linked CsA toxicity. A plethora of recent reports suggest that antioxidants can help reduce many CsA’s adverse effects and therefore might help develop more effective CsA treatment regimens.
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Al-Malki, A.L. and Moselhy, S.S. (2010). The protective effect of epicatchin against oxidative stress and nephrotoxicity in rats induced by cyclosporine. Hum. Exp. Toxicol, [Epub ahead of print].
Amudha, G., Josephine, A., Sudhahar, V. and Varalakshmi, P. (2007). Protective effect of lipoic acid on oxidative and peroxi-dative damage in cyclosporine A-induced renal toxicity. Int. Immunopharmacol, 7, 1442–1449.
Arnadottir, M., Hultberg, B., Vladov, V., Nilsson-Ehle, P. and Thysell, H. (1996). Hyperhomocysteinemia in cyclosporine-treated renal transplant recipients, Transplantation, 61, 509–512.
Baid, S., Cosimi, A.B., Farrell, M.L., Schoenfeld, D.A., Feng, S., Chung, R.T., Tolkoff-Rubin, N. and Pascual, M. (2001). Post-transplant diabetes mellitus in liver transplant recipients: risk factors, temporal relationship with hepatitis C virus allograft hepatitis, and impact on mortality. Transplantation, 72, 1066–1072.
Beckman, J.A., Creager, M.A. and Libby, P. (2002). Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA, 287, 2570–2581.
Behforouz, N.C. and Wenger, CD. (1988). Immunomodulation of murine leishmaniasis with cyclosporin A. Adv. Exp. Med. Biol, 239, 379–384.
Bilchick, K.C., Henrikson, C.A., Skojec, D., Kasper, E.K. and Blumenthal, R.S. (2004). Treatment of hyperlipidemia in cardiac transplant recipients. Am. Heart J., 148, 200–210.
Boots, J.M., Christiaans, M.H. and van Hooff, J.P. (2004). Effect of immunosuppressive agents onlong-term survival of renal transplant recipients: focusonthe cardiovascular risk. Drugs., 64, 2047–2073.
Calne, R.Y., White, D.J., Thiru, S., Evans, D.B., McMaster, P., Dunn, D.C., Craddock, G.N., Pentlow, B.D. Rolles, K. (1978). Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet, 2, 1323–1327.
Capasso, G., Di Gennaro, C.I., Delia Ragione, E., Manna, C., Ciarcia, R., Florio, S., Perna, A., Pollastro, R.M., Damiano, S., Mazzoni, O., Galletti, P. and Zappia, V. (2008). In vivo effect of the natural antioxidant hydroxytyrosol on cyclosporine nephrotoxicity in rats. Nephrol Dial Transplant., 23, 1186–1195.
Chen, C., Jeon, H., Johnston, T.D., Gedaly, R., McHugh, P.P. and Ranjan, D. (2008). Cyclosporin A-induced lipid and protein oxidation in human B-cells and in Epstein-Barr virus-infected B-cells is prevented by antioxidants. J. Invest. Surg., 21, 201–208.
de Arriba, G., de Hornedo, J.P., Rubio, S.R., Fernández, M.C., Martinez, S.B., Camarero, M.M. and Cid, TP. (2009). Vitamin E protects against the mitochondrial damage caused by cyclosporin A in LLC-PK1 cells. Toxicol Appl Pharmacol, 239, 241–250.
Deby, C. and Goutier, R. (1990). New perspectives on the biochemistry of superoxide anion and the efficiency of superoxide dismutases. Biochem. Pharmacol, 39, 399–405.
de Mattos, A.M., Olyaei, A.J. and Bennett, W.M. (2000). Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am. J. Kidney Dis., 35, 333–346.
Diao, T.J., Yuan, T.Y. and Li, YL. (2002). Immunologic role of nitric oxide in acute rejection of golden hamster to rat liver xenotransplantation. World J. Gastroenterol, 8, 746–751.
Doyle, V., Virji, S. and Crompton, M. (1999). Evidence that cyclophilin-A protects cells against oxidative stress. Biochem. J. 341, 127–132.
Hong, F., Lee, J., Song, J.W., Lee, S.J., Ahn, H., Cho, J.J., Ha, J. and Kim, S.S. (2002). Cyclosporin A blocks muscle differentiation by inducing oxidative stress and inhibiting the peptidyl-prolyl-cis-trans isomerase activity of cyclophilin A: cyclophi-lin A protects myoblasts from cyclosporin A-induced cytotoxicity. FASEB J., 16, 1633–1635.
Durak, I., Karabacak, H.I., Buyukkocak, S., Cimen, M.Y., Kacmaz, M., Omeroglu, E. and Ozturk, H.S. (1998). Impaired antioxidant defense system in the kidney tissues from rabbits treated with cyclosporine. Protective effects of vitamins E and C. Nephron, 78, 207–211.
Ebru, U., Burak, U., Yusuf, S., Reyhan, B., Arif, K., Faruk, T.H., Emin, M., Aydin, K., Atilla, I.I., Semsettin, S.nand Kemal, E. (2008). Cardioprotective effects of Nigella sativa oil on cyclosporine A-induced cardiotoxicity in rats. Basic Clin Pharmacol. Toxicol., 103, 574–580.
Erlanger, B.F. (1992). Do we know the site of action of cyclosporin? Immunol. Today, 13, 487–490.
Fraser, A., Veale, DJ. and Emery, P. (2003). Cyclosporin treatment in psoriatic arthritis: a cause of severe leg pain. Ann. Rheum. Dis., 62, 489.
Fridovich, I. (1978). The biology of oxygen radicals. Science, 201, 875–880.
Gökçe, A., Oktar, S., Yönden, Z., Aydin, M., Ilhan, S., Ozkan, O.V., Davarci, M. and Yalçinkaya, F.R. (2009). Protective effect of caffeic acid phenethyl ester on cyclosporine A-induced nephrotoxicity in rats. Ren Fail., 31, 843–847.
Halliwell, B. and Gutteridge, J.M.C. (1999). Free Radicals in Biology and Medicine, Oxford University Press.
Hancock, J.T., Desikan, R. and Neill, S.J. (2001). Role of reactive oxygen species in cell signalling pathways. Biochemical Society Transactions, pp. 345–350.
Herrero, J.I., Quiroga, J., Sangro, B., Beloqui, O., Pardo, F., Cienfuegos, J.A. and Prieto, J. (2000). Hyperhomocysteinemia in liver transplant recipients: prevalence and multivariate analysis of predisposing factors. Liver Transplant., 6, 614–618.
Heydendael, V.M., Spuls, P.I., Opmeer, B.C., de Borgie, C.A., Reitsma, J.B., Goldschmidt, W.F., Bossuyt, P.M., Bos, ID. and de Rie, M.A. (2003). Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl. J. Med., 349, 658–665.
Hjelmesaeth, J., Asberg, A., Muller, F., Hartmann, A. and Jenssen, T. (2005). New-onset posttransplantation diabetes mellitus: insulin resistance or insulinopenia? Impact of immunosuppressive drugs, cytomegalovirus and hepatitis C virus infection. Curr. Diabetes Rev., 1, 1–10.
Ho, S., Clipstone, N., Timmermann, L., Northrop, J., Graef, I., Fiorentino, D., Nourse, J. and Crabtree, G.R. (1996). The mechanism of action of cyclosporin A and FK506. Clin. Immunol. Immunopathol, 80, S40-S45.
Inselmann, G., Barth, A., Engemann, R. and Heidemann, H.T. (1991). Cyclosporin-A induced lipid peroxidation in human liver microsomes and its influence on cytochrome P-450. Eur. J. Clin. Invest., 21, 461–465.
Inselmann, G., Lawerenz, H.U., Nellessen, U. and Heidemann, H.T (1994). Enhancement of cyclosporin A induced hepato-and nephrotoxicity by glutathione depletion. Eur. J. Clin. Invest., 24, 355–359.
Ischiropoulos, H., Gow, A., Thorn, S.R., Kooy, N.W., Royall, J.A. and Crow, J.P. (1999). Detection of reactive nitrogen species using 2,7-dichlorodihydrofluorescein and dihydrorhodamine 123. In Methods in Enzymology: Oxygen Radicals in Biological System (Packer, L., ed.) Academic Press, (Part D) (Vol. 301) pp. 367–373.
Jones, O.T.G. and Hancock, J.T. (2000). Free Radicals in Inflammation (P.G. Winyard, D.R. Blake, C.H. Evans, Eds.), Birkha, Switzerland, pp. 21–46.
Josephine, A., Amudha, G., Veena, C.K., Preetha, S.P. and Varalakshmi, P. (2007). Oxidative and nitrosative stress mediated renal cellular damage induced by cyclosporine A: role of sulphated polysaccharides. Biol. Pharm. Bull., 30, 1254–1259.
Josephine, A., Nithya, K., Amudha, G., Veena, C.K., Preetha, S.P. and Varalakshmi, P. (2008). Role of sulphated polysaccharides from sargassum wightii in cyclosporine A-induced oxidative liver injury in rats. BMC Pharmacol., 8,4.
Josephine, A., Veena, C.K., Amudha, G., Preetha, S.P. and Varalakshmi, P. (2006). Evaluating the effect of sulphated polysaccharides on cyclosporine a induced oxidative renal injury. Mol. Cell. Biochem., 287, 101–108.
Jung, J.Y., Kang, G.C., Jeong, Y.J., Kim, S.H., Kwak, Y.G and Kim, W.J. (2009). Proteomic analysis in cyclosporin A-induced overgrowth of human gingival fibroblasts. Biol. Pharm. Bull, 32, 1480–1485.
Kobashigawa, J.A. and Kasiske, B.L. (1997). Hyperlipidemia in solid organ transplantation. Transplantation, 63, 331–338.
Krauskopf, A., Buetler, T.M., Nguyen, N.S., Macé, K. and Ruegg, U.T (2002). Cyclosporin A-induced free radical generation is not mediated by cytochrome P-450. Br. J. Pharmacol., 135, 977–986.
Kumar, M.S., Xiao, S.G., Fyfe, B., Sierka, D., Heifets, M., Moritz, M.J., Saeed, M.I. and Kumar, A. (2005). Steroid avoidance in renal transplantation using basiliximab induction, cyclosporine-based immunosuppression and protocol biopsies. Clin Transplant., 19, 61–69.
Langford, C.A., Klippel, J.H., Balow, J.E., James, S.P. and Sneller, M.C. (1998a). Use of cytotoxic agents and cyclosporine in the treatment of autoimmune disease. Part 1: rheumatologic and renal diseases. Ann. Intern. Med., 128, 1021–1028.
Langford, C.A., Klippel, J.H., Balow, J.E., James, S.P. and Sneller, M.C. (1998b). Use of cytotoxic agents and cyclosporine in the treatment of autoimmune disease. Part 2: inflammatory bowel disease, systemic vasculitis, and therapeutic toxicity. Ann. Intern. Med., 129, 49–58.
L’Azou, B., Medina, J., Frieauff, W., Cordier, A., Cambar, J. and Wolf, A. (1999). In vitro models to study mechanisms involved in cyclosporine A-mediated glomerular contraction. Arch. Toxicol, 73, 337–345.
Leong, A.C., Yong, J. and Salama, N. (2010). Lymphoprolifera-tive disorder of nasopharynx after long-standing cyclosporin therapy for psoriatic arthritis. J. Laryngol. Otol., 7, 1–3.
Lichtiger, S., Present, D.H., Kornbluth, A., Gelernt, I., Bauer, J., Galler, G., Michelassi, F. and Hanauer, S. (1994). Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl. J. Med., 330, 1841–1845.
Louie, B., Rajamahanty, S., Pyo, P., Choudhury, M. and Konno, S. (2010). Mode of cytotoxic action of nephrotoxic agents: oxidative stress and glutathione-dependent enzyme. BJU Int., 105, 264–268.
Malyszko, J., Malyszko, J.S., Pawlak, K. and Mysliwiec, M. (1996). The coagulo-lytic system and endothelial function in cyclosporine-treated kidney allograft recipients. Transplantation, 62, 828–830.
Marchetti, P. (2004). New-onset diabetes after transplantation. J. Heart Lung Transplant., 23, S194-S201.
Mason, J. (1990). The pathophysiology of Sandimmune (cyclospo-rine) in man and animals. Pediatr. Nephrol., 4, 686–704.
McGrath, L.T., Treacy, R., McClean, E. and Brown, LH. (1997). Oxidative stress in cyclosporin and azathioprine treated renal transplant patients. Clin. Chim. Acta, 264, 1–12.
Moien-Afshari, F., McManus, B.M. and Laher, I. (2003). Immunosuppression and transplant vascular disease: benefits and adverse effects. Pharmacol. Ther., 100, 141–156.
Mostafavi-Pour, Z., Zal, R., Monabati, A. and Vessal, M. (2008). Protective effects of a combination of quercetin and vitamin E against cyclosporine A-induced oxidative stress and hepatotox-icity in rats. Hepatol. Res., 38, 385–392.
Mourad, G., Vela, C., Ribstein, J. and Mimran, A. (1998). Long-term improvement in renal function after cyclosporine reduction in renal transplant recipients with histologically proven chronic cyclosporine nephropathy. Transplantation, 65, 661–667.
Myers, B.D., Sibley, R., Newton, L., Tomlanovich, S.J., Boshkos, C., Stinson, E., Luetscher, J.A., Whitney, D.J., Krasny, D. and Coplon, N.S. (1988). The long-term course of cyclosporine-associated chronic nephropathy. Kidney Int., 33, 590–600.
Nankivell, B.J., Borrows, R.J., Fung, C.L., O’Connell, P.J., Allen, R.D. and Chapman, J.R (2003). The natural history of chronic allograft nephropathy. NEngl. J. Med., 349, 2326–2333.
Olyaei, A.J., de Mattos, A.M. and Bennett, W.M. (2001). Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies. Curr. Opin. Crit. Care., 7, 384–389.
Pari, L. and Sivasankari, R. (2008). Effect of ellagic acid on cyclosporine A-induced oxidative damage in the liver of rats. Fundam Clin Pharmacol., 22, 395–401.
Parra Cid, T., Conejo Garcia, J.R., Carballo Alvarez, R. and de Arriba, G. (2003). Antioxidant nutrients protect against cyclosporine A nephrotoxicity. Toxicology, 189, 99–111.
Parra, T., de Arriba, G., Arribas, I., Perez de Lema, G., Rodriguez-Puyol, D. and Rodriguez-Puyol, M. (1998a). Cyclosporine A nephrotoxicity: role of thromboxane and reactive oxygen species. J. Lab. Clin. Med., 131, 63–70.
Parra, T., de Arriba, G., Conejo, J.R., Cantero, M., Arribas, I., Rodriguez-Puyol, D., Rodriguez-Puyol, M. and Carballo, R., (1998b). Cyclosporine increases local glomerular synthesis of reactive oxygen species in rats: effect of vitamin E on cyclosporine nephrotoxicity. Transplantation, 66, 1325–1329.
Pascual, M., Theruvath, T., Kawai, T., Tolkoff-Rubin, N. and Cosimi, A.B. (2002). Strategies to improve long-term outcomes after renal transplantation. N Engl. J. Med., 346, 580–590.
Perez de Lema, G., Arribas-Gomez, I., Ruiz-Gines, J.A., de Arriba, G., Prieto, A., Rodriguez-Puyol, D. and Rodriguez-Puyol, M., (1997). Reactive oxygen species mediate the effects of cyclosporine A on human cultured mesangial cells. Transplant. Proc, 29, 1241–1243.
Perez de Lema, G., Arribas, I., Prieto, A., Parra, T., de Arriba, G., Rodriguez-Puyol, D. and Rodriguez-Puyol, M. (1998). Cyclosporin A-induced hydrogen peroxide synthesis by cultured human mesangial cells is blocked by exogenous antioxidants. Life Sci., 62, 1745–1753.
Pickrell, M.D., Sawers, R. and Michael, J. (1988). Pregnancy after renal transplantation: severe intrauterine growth retardation during treatment with cyclosporin A. Br. Med. J., 19, 825.
Racusen, L.C., Kone, B.C. and Solez, K. (1987). Early renal pathophysiology in an acute model of cyclosporine nephrotoxicity in rats. Ren Fail, 10, 29–37.
Reis, R., Rocha-Pereira, P., Teixeira de Lemos, E., Parada, B., Baptista, S., Figueiredo, A., Santos-Silva, A., Costa-Almeida, C., Mota, A. and Teixeira, F. (2007). Oxidative stress in cyclospo-rine-induced hypertension: evidence of beneficial effects or tolerance development with nitrate therapy. Transplant Proc, 39, 2494–500.
Rezzani, R. (2004). Cyclosporine A and adverse effects on organs: histochemical studies. Prog. Histochem. Cytochem., 39, 85–128.
Rezzani, R. (2006). Exploring cyclosporine A-side effects and the protective role-played by antioxidants: the morphological and immunohistochemical studies. Histol Histopathol., 21, 301–16.
Rezzani, R., Rodella, L.F., Fraschini, F., Gasco, M.R., Demartini, G., Musicanti, C. and Reiter, RJ. (2009). Melatonin delivery in solid lipid nanoparticles: prevention of cyclosporine A induced cardiac damage. J. Pineal. Res., 46, 255–261.
Romero, M., Garcia-Monzon, C., Clemente, G., Salcedo, M., Alvarez, E., Majano, P.L. and Moreno-Otero, R. (2001). Intrahepatic expression of inducible nitric oxide synthase in acute liver allograft rejection: evidence of modulation by corticosteroids. Liver-Transplantation., 7, 16–21.
Shaw, K.T., Ho, A.M., Raghavan, A., Kim, J., Jain, J., Park, J., Sharma, S., Rao, A. and Hogan, P.G. (1995). Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells. Proc. Natl. Acad. Sci. USA, 92, 11205–11209.
Shen, S.Y., Weir, M.R., Revie, D.R., Dagher, F.J., Bentley, F.R. and Chretien, PB. (1987). Differentiation of acute rejection from acute cyclosporine nephrotoxicity in renal transplants peripheral T cell subset counts. Transplant Proc, 19, 1776–1779.
Markell, M., Armenti, V., Danovitch, G. and Sumrani, N. (1994). Hyperlipidemia and glucose intolerance in the post-renal transplant patient. J. Am. Soc. Nephrol, 4, S37-S47.
Stallone, G., Infante, B., Schena, A., Di Paolo, S., Grandaliano, G., Gesualdo, L. and Schena, F.P. (2004). Cardiovascular risk and renal transplantation. G. Ital. Nefrol., 21, 144–155.
Suthanthiran, M., Morris, RE. and Strom, T.B. (1996). Immunosuppressants: cellular and molecular mechanisms of action. Am. J. Kidney Dis., 28, 159–172.
Taylor, A.L., Watson, C.J. and Bradley, J.A. (2005). Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy. Crit. Rev. Oncol. Hematol., 56, 23–46.
ten Brinke, A., Zwinderman, A.H., Sterk, P.J., Rabe, K.F. and Bel, E.H. (2004). “Refractory” eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids. Am. J. Respir Crit. Care Med., 170, 601–605.
Tugwell, P., Pincus, T., Yocum, D., Stein, M., Gluck, O., Kraag, G., McKendry, R., Tesser, J., Baker, P. and Wells, G. (1995). Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The methotrexate-cyclosporine combination study group. N Engl J Med., 333, 137–141.
Watkins, P.B. (1990). The role of cytochromes P-450 in cyclosporine metabolism. J. Am. Acad. Dermatol., 23, 1301–1309.
Weber, A.J., Soong, G., Bryan, R., Saba, S. and Prince, A. (2001). Activation of NF-kappaB in airway epithelial cells is depen- dent on CFTR trafficking and Cl- channel function. Am. J. Physiol. Lung Cell. Mol. Physiol, 281, L71-L78.
Yilce, A., Atessahin, A. and Ceribasi, A.O. (2008). Amelioration of cyclosporine A-induced renal, hepatic and cardiac damages by ellagic acid in rats. Basic Clin. Pharmacol. Toxicol., 103, 186–91.
Young, B.A., Burdmann, E.A., Johnson, R.J., Alpers, C.E., Giach- elli, C.M., Eng, E., Andoh, T., Bennett, W.M. and Couser, W.G. (1995a). Cellular proliferation and macrophage influx precede interstitial fibrosis in cyclosporine nephrotoxicity. Kidney Int., 48, 439–448.
Young, B.A., Burdmann, E.A., Johnson, R.J., Andoh, T., Bennett, W.M., Couser, W.G. and Alpers, C.E. (1995b). Cyclosporine A induced arteriolopathy in a rat model of chronic cyclosporine nephropathy. Kidney Int., 48, 431–438.
Zhong, Z., Arteel, G.E., Connor, H.D., Yin, M., Frankenberg, M.V., Stachlewitz, R.F., Raleigh, J.A., Mason, R.P. and Thurman, R.G. (1998). Cyclosporin A increases hypoxia and free radical production in rat kidneys: prevention by dietary glycine. Am. J. Physiol, 275, F595–F604.
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Lee, J. Use of Antioxidants to Prevent Cyclosporine A Toxicity. Toxicol Res. 26, 163–170 (2010). https://doi.org/10.5487/TR.2010.26.3.163
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DOI: https://doi.org/10.5487/TR.2010.26.3.163