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Protective effect of mycophenolate mofetil against nephrotoxicity and hepatotoxicity induced by tacrolimus in Wistar rats

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Abstract

Tacrolimus (TAC), a calcineurin inhibitor (CNI), is clinically used as an immunosuppressive agent in the transplant recipient; however, the use of TAC is greatly limited by its nephrotoxicity and hepatotoxicity. Mycophenolate mofetil (MMF), an inhibitor of the purine synthesis, has been used in combination with many immunosuppressive drugs such as TAC. The association TAC/MMF was used in organ transplantation to increase the efficiency and reduce acute rejection rates, but the effects of MMF on TAC-induced kidney and liver injuries are still not well investigated. The aims of this study are to explore whether MMF co-administration with TAC has a renoprotective and hepatoprotective effect against TAC-induced renal and hepatic injuries and to check the implication of oxidative stress in the MMF’s possible protective effect. Our results showed that MMF (at 50 mg kg−1 body weight (b.w.)) restored creatinine, in addition to increased AST and ALT levels by TAC (at 60 mg kg−1 b.w.). Furthermore, MMF decreased DNA damage induced by TAC in the kidney and liver of rats as assessed by comet assay. This renoprotective and hepatoprotective effect of MMF was associated with an antioxidant effect. In fact, MMF co-treatment with TAC decreased oxidative damage induced by TAC. It reduced malondialdehyde (MDA) and protein carbonyl (PC) levels as well as catalase and superoxide dismutase (SOD) activities. We conclude that the co-administration MMF with TAC protect liver and kidney against TAC toxicity via an antioxidant process.

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References

  1. Al-Harbi NO, Imam F, Al-Harbi MM, Iqbal M, Nadeem A, Al-Shahrah OA, Korashy HM, Al-Hosaini KA, Ahmed M, Bahashwar S (2014) Treatment with aliskiren ameliorates tacrolimus-induced nephrotoxicity in rats. J Renin Angiotensin Aldosterone Syst

  2. Al-Harbi NO, Imam F, Al-Harbi MM, Iqbal M, Nadeem A, Sayed-Ahmed MM, Alabidy AD, Almukhallafi AF (2014) Olmesartan attenuates tacrolimus-induced biochemical and ultrastructural changes in rat kidney tissue. Biomed Res Int 2014:607246

    Article  PubMed  PubMed Central  Google Scholar 

  3. Allison AC, Eugui EM (2000) Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 47:85–118

    Article  CAS  PubMed  Google Scholar 

  4. Amin A, Hamza AA (2005) Oxidative stress mediates drug-induced hepatotoxicity in rats: a possible role of DNA fragmentation. Toxicology 208:367–375

    Article  CAS  PubMed  Google Scholar 

  5. Aust SD (1989) Metal ions, oxygen radicals and tissue damage. Bibl Nutr Dieta 43:266–277

    PubMed  Google Scholar 

  6. Beckebaum S, Cicinnati VR, Klein CG, Brokalaki E, Yu Z, Malago M, Frilling A, Gerken G, Broelsch CE (2004) Impact of combined mycophenolate mofetil and low-dose calcineurin inhibitor therapy on renal function, cardiovascular risk factors, and graft function in liver transplant patients: preliminary results of an open prospective study. Transplant Proc 36:2671–2674

    Article  CAS  PubMed  Google Scholar 

  7. Beyer WE, Fridovich I (1987) Assaying for superoxide dismutase activity: some large consequences of minor changes in conditions. Anal Biochem 161:559–566

    Article  CAS  PubMed  Google Scholar 

  8. Bradford MM (1976) A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  9. Christians U, Kruse C, Kownatzki R, Schiebel HM, Schwinzer R, Sattler M, Schottmann R, Linck A, Almeida VM, Braun F (1991) Measurement of FK 506 by HPLC and isolation and characterization of its metabolites. Transplant Proc 23:940–941

    CAS  PubMed  Google Scholar 

  10. Clairbone A (1985) Catalase activity. Handbook of methods for oxygen radical research. CRC, Boca Raton, pp 283–284

    Google Scholar 

  11. Collins AR, Dusinska M, Gedik CM, Stetina R (1996) Oxidative damage to DNA: do we have a reliable biomarker? Environ Health Perspect 104:465–469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Creput C, Blandin F, Deroure B, Roche B, Saliba F, Charpentier B, Samuel D, Durrbach A (2007) Long-term effects of calcineurin inhibitor conversion to mycophenolate mofetil on renal function after liver transplantation. Liver Transpl 13:1004

    Article  PubMed  Google Scholar 

  13. Dalal P, Shah G, Chhabra D, Gallon L (2010) Role of tacrolimus combination therapy with mycophenolate mofetil in the prevention of organ rejection in kidney transplant patients. Int J Nephrol Renov Dis 3:107–115

    CAS  Google Scholar 

  14. Engl T, Makarevi TJ, Relja B, Natsheh I, Müller I, Jonas D, Beecken WD, Blaheta RA (2005) Mycophenolate mofetil modulates adhesion receptors of the beta1 integrin family on tumor cells: impact on tumor recurrence and malignancy. BMC Cancer 5:4

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ferjani H, Achour A, Bacha H, Abid S (2015) Tacrolimus and mycophenolate mofetil associations: induction of oxidative stress or antioxidant effect? Hum Exp Toxicol

  16. Fernandes MB, Caldas HC, Toloni LD, Baptista MA, Fernandes IM, Abbud-Filho M (2014) Supplementation with omega-3 polyunsaturated fatty acids and experimental tacrolimus-induced nephrotoxicity. Exp Clin Transplant 12:522–527

    PubMed  Google Scholar 

  17. Fréguin-Bouilland C, Godin M, Bellien J, Richard V, Remy-Jouet I, Dautreaux B, Henry JP, Compagnon P, Thuillez C, Plissonnier D, Joannidès R (2011) Protective effect of mycophenolate mofetil on endothelial function in an aortic allograft model. Transplantion 91:35–41

    Article  Google Scholar 

  18. Ganschow R, Albani J, Grabhorn E, Richter A, Burdelski M (2006) Tacrolimus-induced cholestatic syndrome following pediatric liver transplantation and steroid-resistant graft rejection. Pediatr Transplant 10:220

    Article  CAS  PubMed  Google Scholar 

  19. Gonzalez-Molina M, Ruiz-Esteban P, Burgos D, Rodriguez MA, Cabello M, Gutierrez E, Hernandez D (2012) Mycophenolate mofetil and tacrolimus reduce mortality after deceased donor kidney transplantation. Transplant Proc 44:2577–2578

    Article  CAS  PubMed  Google Scholar 

  20. Hortelano S, Castilla M, Torres AM, Tejedor A, Boscá L (2000) Potentiation by nitric oxide of cyclosporin A and FK506-induced apoptosis in renal proximal tubule cells. J Am Soc Nephrol 11:2315–2323

    CAS  PubMed  Google Scholar 

  21. Hubner GI, Eismann R, Sziegoleit W (1999) Drug interaction between mycophenolate mofetil and tacrolimus detectable within therapeutic mycophenolic acid monitoring in renal transplant patients. Ther Drug Monit 21:536–539

    Article  CAS  PubMed  Google Scholar 

  22. Ibrahim MA, Ashour OM, Ibrahim YF, El-Bitar HI, Gomaa W, Abdel-Rahim SR (2009) Angiotensin-converting enzyme inhibition and angiotensin AT1-receptor antagonism equally improve doxorubicin-induced cardiotoxicity and nephrotoxicity. Pharmacol Res 60:373–381

    Article  CAS  PubMed  Google Scholar 

  23. Iwasaki K, Shiraga T, Matsuda H, Nagase K, Tokuma Y, Hata T, Fujii Y, Sakuma S, Fujitsu T, Fujikawa A (1995) Further metabolism of FK506 (tacrolimus). identification and biological activities of the metabolites oxidized at multiple sites of FK506. Drug Metab Dispos 23:28–34

    CAS  PubMed  Google Scholar 

  24. Iwasaki K, Shiraga T, Nagase K, Tozuka Z, Noda K, Sakuma S, Fujitsu T, Shimatani K, Sato A, Fujioka M (1993) Isolation, identification, and biological activities of oxidative metabolites of FK506, a potent immunosuppressive macrolide lactone. Drug Metab Dispos 21:971–977

    CAS  PubMed  Google Scholar 

  25. Johnson LB, Kuo PC, Dafoe DC, Drachenberg CB, Schweitzer EJ, Alfrey EJ, Ridge LA, Salvatierra P, Papadimitriou JC, Mergner WJ, Bartlett ST (1996) The use of bilateral adult renal allografts—a method to optimize function from donor kidneys with suboptimal nephron mass. Transplantation 61:1261–1263

    Article  CAS  PubMed  Google Scholar 

  26. Karabulut AB, Ara C (2009) Melatonin ameliorates tacrolimus (FK-506)’s induced immunosuppressive effect in rat liver. Transplant Proc 41(5):1875–1877

    Article  CAS  PubMed  Google Scholar 

  27. Khanna AK, Pieper GM (2007) NADPH oxidase subunits (NOX-1, p22phox, Rac-1) and tacrolimus-induced nephrotoxicity in a rat renal transplant model. Nephrol Dial Transplant 22:376–385

    Article  CAS  PubMed  Google Scholar 

  28. Klawitter J, Klawitter J, Schmitz V, Shokati T, Epshtein E, Thurman JM, Christians U (2014) Mycophenolate mofetil enhances the negative effects of sirolimus and tacrolimus on rat kidney cell metabolism. PLoS One 9:e86202

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ko MS, Choi YH, Jung SH, Lee JS, Kim HS, Lee CH, Kim SG (2015) Tacrolimus therapy causes hepatotoxicity in patients with a history of liver disease. Int J Clin Pharmacol Ther 53:363–371

    Article  CAS  PubMed  Google Scholar 

  30. Kino T, Goto T (1993) Discovery of FK-506 and update. Ann N Y Acad Sci 685:13–21

    Article  CAS  PubMed  Google Scholar 

  31. Mercier Y, Gatellier P, Renerre M (2004) Lipid and protein oxidation in vitro, and antioxidant potential in meat from Charolais cows finished on pasture or mixed diet. Meat Sci 66:467–473

    Article  CAS  PubMed  Google Scholar 

  32. Meier-Kriesche HU, Li S, Gruessner RW, Fung JJ, Bustami RT, Barr ML, Leichtman AB (2006) Immunosuppression: evolution in practice and trends, 1994–2004. Am J Transplant 6:1111–1131

    Article  CAS  PubMed  Google Scholar 

  33. Mesar I, Kes P, Hudolin T, Basic-Jukic N (2013) Rescue therapy with sirolimus in a renal transplant recipient with tacrolimus-induced hepatotoxicity. Ren Fail 35:1434–1435

    Article  CAS  PubMed  Google Scholar 

  34. Nieto E, Escudero E, Navarro E, Yanez-Mo M, Martin A, Perez de Lema G, Sanchez-Madrid F, Mampaso F (2002) Effects of mycophenolate mofetil in mercury-induced autoimmune nephritis. J Am Soc Nephrol 13:937–945

    CAS  PubMed  Google Scholar 

  35. Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, Arndorfer J, Christensen L, Merion RM (2003) Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 349:931–940

    Article  CAS  PubMed  Google Scholar 

  36. Oto T, Okazaki M, Takata K, Egi M, Yamane M, Toyooka S, Sano Y, Snell GI, Goto K, Miyoshi S (2010) Calcineurin inhibitor-related cholestasis complicating lung transplantation. Ann Thorac Surg 89:1664

    Article  PubMed  Google Scholar 

  37. Picada JN, Flores DG, Zettler CG, Marroni NP, Roesler R, Henriques JA (2003) DNA damage in brain cells of mice treated with an oxidized form of apomorphine. Mol Brain Res 114:80–85

    Article  CAS  PubMed  Google Scholar 

  38. Randhawa MA (2009) Calculation of LD50 values from the method of Miller and Tainter, 1944. J Ayub Med Coll Abbottabad J21(3):184–185

    Google Scholar 

  39. Saad SY, Arafah MM, Najjar TA (2007) Effects of mycophenolate mofetil on cisplatin-induced renal dysfunction in rats. Cancer Chemother Pharmacol 59:455–460

    Article  CAS  PubMed  Google Scholar 

  40. Sacher VY, Bejarano PA, Pham SM (2012) Tacrolimus induced hepatotoxicity in a patient with bilateral lung transplant. Transpl Int 25:e111–e112

    Article  PubMed  Google Scholar 

  41. Singh NP, McCoy MT, Tice RR, Schneider EL (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175:184–191

    Article  CAS  PubMed  Google Scholar 

  42. Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramanan R, Jain A (1989) FK 506 for human liver kidney and pancreas transplantation. Lancet 2:1000–1004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Stillman IE, Andoh TF, Burdmann EA, Bennett WM, Rosen S (1995) FK506 nephrotoxicity: morphologic and physiologic characterization of a rat model. Lab Investig 73:794–803

    CAS  PubMed  Google Scholar 

  44. Tada H, Nakashima A, Awaya A, Fujisaki A, Inoue K, Kawamura K, Itoh K, Masuda H, Suzuki T (2002) Effects of thymic hormone on reactive oxygen species-scavengers and renal function in tacrolimus-induced nephrotoxicity. Life Sci 70:1213–1223

    Article  CAS  PubMed  Google Scholar 

  45. Taniai N, Akimaru K, Ishikawa Y, Kanada T, Kakinuma D, Mizuguchi Y, Mamada Y, Yoshida H, Tajiri T (2008) Hepatotoxicity caused by both tacrolimus and cyclosporine after living donor liver transplantation. J Nippon Med Sch 75:187–191

    Article  PubMed  Google Scholar 

  46. Thomson AW, Bonham CA, Zeevi (1995) Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit 17:584–591

    Article  CAS  PubMed  Google Scholar 

  47. Tice RR, Agurell E, Anderson D, Burlinson B, Hartmann A, Kobayashi H, Miyamae Y, Rojas E, Ryu JC, Sasaki YF (2000) The single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen 35:206–221

    Article  CAS  PubMed  Google Scholar 

  48. Tuñón MJ, Sánchez-Campos S, Gutiérrez B, Culebras JM, González-Gallego J (2003) Effects of FK506 and rapamycin on generation of reactive oxygen species, nitric oxide production and nuclear factor kappa B activation in rat hepatocytes. Biochem Pharmacol 66(3):439–445

    Article  PubMed  Google Scholar 

  49. Vincenti F, Laskow DA, Neylan JF, Mendez R, Matas AJ (1996) One-year follow-up of an open-label trial of FK506 for primary kidney transplantation. Transplantation 61:1576–1581

    Article  CAS  PubMed  Google Scholar 

  50. Wenceslau CF, McCarthy CG, Szasz T, Spitler K, Goulopoulou S, Webb RC, Working Group on DAMPs in Cardiovascular Disease (2014) Mitochondrial damage-associated molecular patterns and vascular function. Eur Heart J 35:1172–1177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yadav DK, Gera DN, Gumber MR, Kute VB, Patel MP, Vanikar AV, Trivedi HL (2013) Tacrolimus-induced severe cholestasis complicating renal transplantation. Ren Fail 35:735–737

    Article  PubMed  Google Scholar 

  52. Zucker K, Rosen A, Tsaroucha A, de Faria L, Roth D, Ciancio G, Esquenazi V, Burke G, Tzakis A, Miller J (1997) Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings. Transplant Immunol 5:225–232

    Article  CAS  Google Scholar 

  53. Zucker K, Tsaroucha A, Olson L, Esquenazi V, Tzakis A, Miller J (1999) Evidence that tacrolimus augments the bioavailability of mycophenolate mofetil through the inhibition of mycophenolic acid glucuronidation. Ther Drug Monit 21:35–43

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This research was supported by the “Ministère Tunisien de l’enseignement Supérieur, de la Recherche Scientifique et des Technologies de l’Information et de la Communication” through the “Laboratoire de Recherche sur les Substances Biologiquement Compatibles” (LRSBC).

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Correspondence to Hassen Bacha.

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Ferjani, H., El Arem, A., Bouraoui, A. et al. Protective effect of mycophenolate mofetil against nephrotoxicity and hepatotoxicity induced by tacrolimus in Wistar rats. J Physiol Biochem 72, 133–144 (2016). https://doi.org/10.1007/s13105-015-0451-7

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