Skip to main content

Therapeutic effect of N-acetylcysteine on chemotherapy-induced liver injury

Irish Journal of Medical Science (1971 -) volume 189, pages 1189–1194 (2020)Cite this article

Abstract

Background

N-acetylcysteine (NAC) may be useful in the management of chemotherapy-induced liver injury.

Aims

The present study evaluates the possible therapeutic effects of NAC on chemotherapy-induced hepatotoxicity.

Methods

A total of 102 patients’ files who were diagnosed with cancer between 2015 and 2019 were evaluated retrospectively. Two patient groups with and without NAC were selected. NAC was administered in a 3-μg/kg IV dose in a 24-h infusion to 70 patients when any alanine aminotransferase (ALT) or gamma-glutamyl transferase (GGT) values reached three times the normal levels. The other group consisted of 32 patients who were not treated with NAC. Alanine aminotransferase and GGT values were recorded at pretreatment, and on the 1st, 3rd, 5th, and 7th days in both the NAC and non-NAC groups from files.

Results

In the NAC group, ALT and GGT values on day 1, 3, 5, and 7 differed from each other, decreasing from day 1 to day 7. A statistically significant difference was noted between the values in the NAC group (p < 0.001). In the non-NAC group, the ALT values on day 7 were lower than the ALT values on day 1. A comparison of the ALT and GGT values in the NAC and non-NAC groups found that the values in the NAC group decreased earlier than in the non-NAC group.

Conclusions

This study shows that NAC has a therapeutic effect on hepatotoxicity in children being treated with chemotherapeutic agents due to underlying malign diseases. The early reduction in the results of liver function tests is important for the continuation of chemotherapy.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

References

  1. Ranjeeta B, Rajender Reddy K (2014) Drug-induced liver injury due to cancer chemotherapeutic agents. Semin Liver Dis 34:162–171. https://doi.org/10.1055/s-0034-1375957

    Article  CAS  Google Scholar 

  2. Sabuncuoğlu S, Ozgunes H (2011) Chemotherapy, free radicals and oxidative stress. Hacet Univ Fac Pharm J 31:137–150

    Google Scholar 

  3. Weijl NI, Cleton FJ, Osanto S (1997) Free radicals and antioxidants in chemotherapy-induced toxicity. Cancer Treat Rev 23:209–240. https://doi.org/10.1016/s0305-7372(97)90012-8

    Article  CAS  PubMed  Google Scholar 

  4. Crohns M, Liippo K, Erhola M et al (2009) Concurrent decline of several antioxidants and markers of oxidative stress during combination chemotherapy for small cell lung cancer. Clin Biochem 42:1236–1245. https://doi.org/10.1016/j.clinbiochem.2009.05.003

    Article  CAS  PubMed  Google Scholar 

  5. Simone CB, Simone NL, Simone V (2007) Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival. Altern Ther Health Med 13:22–28

    PubMed  Google Scholar 

  6. Facorro G, SarrasagueMM TH, Hager A et al (2004) Oxidative study of patients with total body irradiation: effects of amifostine treatment. Bone Marrow Transplant 33:793–798. https://doi.org/10.1038/sj.bmt.1704427

    Article  CAS  PubMed  Google Scholar 

  7. Chen Y, JungsuwadeP VM, Butterfield DA, St Clair DK (2007) Collateral damage in cancer chemotherapy: oxidative stress in nontargeted tissues. Mol Interv 7:147–156. https://doi.org/10.1124/mi.7.3.6

    Article  CAS  PubMed  Google Scholar 

  8. SariI CA, Kaynar L, Saraymen R et al (2008) Disturbance of pro-oxidative/antioxidative balance in allogeneic peripheral blood stem cell transplantation. Ann Clin Lab Sci 38:120–125

    Google Scholar 

  9. Brea-Calvo G, Rodríguez-Hernández A, Fernández-Ayala et al (2006) Chemotherapy induces an increase in coenzyme Q10 levels in cancer cell lines. Free Radic Biol Med 40:1293–1302. https://doi.org/10.1016/j.freeradbiomed.2005.11.014

    Article  CAS  PubMed  Google Scholar 

  10. Sangeetha P, Das UN, Koratkar R, Suryaprabha P (1990) Increase in free radical generation and lipid peroxidation following chemotherapy in patients with cancer. Free Radic Biol Med 8:15–19. https://doi.org/10.1016/0891-5849(90)90139-a

    Article  CAS  PubMed  Google Scholar 

  11. White AC, Sousa AM, Blumberg J et al (2006) Plasma antioxidants in subjects before hematopoietic stem cell transplantation. Bone Marrow Transplant 38:513–520. https://doi.org/10.1038/sj.bmt.1705475

    Article  CAS  PubMed  Google Scholar 

  12. Clemens MR, Waladkhani AR, Bublitz K et al (1997) Supplementation with antioxidants prior to bone marrow transplantation. Wien Klin Wochenschr 109:771–776

    CAS  PubMed  Google Scholar 

  13. Fridovich I (1983) Superoxide radical: an endogenous toxicant. Annu Rev Pharmacol Toxicol 23:239–257. https://doi.org/10.1146/annurev.pa.23.040183.001323

    Article  CAS  PubMed  Google Scholar 

  14. Sugiyama S, Hayakawa M, Kato T et al (1989) Adverse effects of anti-tumor drug, cisplatin, on rat kidney mitochondria: disturbances in glutathione peroxidase activity. Biochem Biophys Res Commun 159:1121–1127. https://doi.org/10.1016/0006-291x(89)92225-0

    Article  CAS  PubMed  Google Scholar 

  15. Zhang JG, Zhong LF, Zhang M, Xia YX (1992) Protection effects of procaine on oxidative stress and toxicities of renal cortical slices from rats caused by cisplatin in vitro. Arch Toxicol 66:354–358. https://doi.org/10.1007/bf01973631

    Article  CAS  PubMed  Google Scholar 

  16. Gill RA, Onstad GR, Cardamone JM et al (1982) Hepatic veno-occlusive disease caused by 6-thioguanine. Ann Intern Med 96:58–60. https://doi.org/10.7326/0003-4819-96-1-58

    Article  CAS  PubMed  Google Scholar 

  17. Stoneham S, Lennard L, Coen P et al (2003) Veno-occlusive disease in patients receiving thiopurines during maintenance therapy for childhood acute lymphoblastic leukemia. Br J Haematol 123:100–102. https://doi.org/10.1046/j.1365-2141.2003.04578.x

    Article  PubMed  Google Scholar 

  18. Lee WM (1995) Drug-induced hepatotoxicity. N Engl J Med 333:1118–1127. https://doi.org/10.1056/NEJM199510263331706

    Article  CAS  PubMed  Google Scholar 

  19. DeLeve LD, Shulman HM, McDonald GB (2002) Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis 22:27–42. https://doi.org/10.1055/s-2002-23204

    Article  PubMed  Google Scholar 

  20. Chughlay MF, Kramer N, Spearman CV et al (2016) N-acetylcysteine for non-paracetamol drug induced liver injury: a systematic review. Br J Clin Pharmacol 81:1021–1029. https://doi.org/10.1111/bcp.12880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Koren G, Beatty K, Seto A et al (1992) The effects of impaired liver function on the elimination of antineoplastic agents. Ann Pharmacother 26:363–371. https://doi.org/10.1177/106002809202600311

    Article  CAS  PubMed  Google Scholar 

  22. Desai ZR, Van den Berg HW, Bridges JM, Shanks RG (1982) Can severe vincristine neurotoxicity be prevented? Cancer Chemother Pharmacol 8:211–214. https://doi.org/10.1007/bf00255486

    Article  CAS  PubMed  Google Scholar 

  23. Hohneker JA (1994) A summary of vinorelbine (Navelbine) safety datafrom north American clinical trials. Semin Oncol 21:42–46

    CAS  PubMed  Google Scholar 

  24. Van den Berg HW, Desai ZR, Wilson R et al (1982) The pharmacokinetics of vincristine in man: reduced drug clearance associated with raised serum alkaline phosphatase and dose-limited elimination. Cancer Chemother Pharmacol 8:215–219. https://doi.org/10.1007/bf00255487

    Article  PubMed  Google Scholar 

  25. Stewart CF, Arbuck SG, Fleming RA, Evans WE (1990) Changes in the clearance of total and unbound etoposide in patients with liver dysfunction. J Clin Oncol 8:1874–1879. https://doi.org/10.1200/JCO.1990.8.11.1874

    Article  CAS  PubMed  Google Scholar 

  26. Raymond E, Boige V, Faivre S et al (2002) Dosage adjustment and pharmacokinetic profile of irinotecan in cancer patients with hepatic dysfunction. J Clin Oncol 20:4303–4312. https://doi.org/10.1200/JCO.2002.03.123

    Article  CAS  PubMed  Google Scholar 

  27. Neuman MG, Cameron RG, Haber JA et al (1999) Inducers of cytochrome P450 2E1 enhance methotrexate-induced hepatocytoxicity. Clin Biochem 32:519–536. https://doi.org/10.1016/s0009-9120(99)00052-1

    Article  CAS  PubMed  Google Scholar 

  28. Jahovic N, Cevik H, Sehirli AO et al (2003) Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats. J Pineal Res 34:282–287

    Article  CAS  Google Scholar 

  29. Cetiner M, Sener G, Sehirli AO et al (2005) Taurine protects against methotrexate-induced toxicity and inhibits leukocyte death. Toxicol Appl Pharmacol 209:39–50. https://doi.org/10.1016/j.taap.2005.03.009

    Article  CAS  PubMed  Google Scholar 

  30. Ali N, Rashid S, Nafees S et al (2017) Protective effect of chlorogenic acid against methotrexate induced oxidative stress, inflammation and apoptosis in rat liver: an experimental approach. Chem Biol Interact 272:80–91. https://doi.org/10.1016/j.cbi.2017.05.002

    Article  CAS  PubMed  Google Scholar 

  31. Szabo S (1984) Role of sulfhydryls and early vascular lesions in gastric mucosal injury. Acta Physiol Hung 64:203–214

    CAS  PubMed  Google Scholar 

  32. Ross D (1988) Glutathione, free radicals and chemotherapeutic agents. Mechanisms of free-radical induced toxicity and glutathione-dependent protection. Pharmacol Ther 37:231–249. https://doi.org/10.1016/0163-7258(88)90027-7

    Article  CAS  PubMed  Google Scholar 

  33. Babiak RM, Campello AP, Carnieri EG (1998) Methotrexate: pentose cycle and oxidative stress. Cell Biochem Funct 16:283–293. https://doi.org/10.1002/(SICI)1099-0844(1998120)16:4<283::AID-CBF801>3.0.CO;2-E

    Article  CAS  PubMed  Google Scholar 

  34. Manov I, Hırsh M, Iancu TC (2002) Acetaminophen hepatotoxicity and mechanisms of its protection by N-acetylcysteine: a study of Hep3B cells. Exp Toxicol Pathol 53:489–500. https://doi.org/10.1078/0940-2993-00215

    Article  CAS  PubMed  Google Scholar 

  35. Kumar O, Sugendran K, Vijayaraghavan R (2003) Oxidative stress associated hepatic and renal toxicity induced by ricin in mice. Toxicon 1:333–338. https://doi.org/10.1016/s0041-0101(02)00313-6

    Article  Google Scholar 

  36. Akhgari M, Abdollahi M, Kebryaeezadeh A et al (2003) Biochemical evidence for free radical-induced lipid peroxidation as a mechanism for subchronic toxicity of malathion in blood and liver of rats. Hum Exp Toxicol 22:205–211. https://doi.org/10.1191/0960327103ht346oa

    Article  CAS  PubMed  Google Scholar 

  37. Tafazoli S, Spehar DD, O’Brien PJ (2005) Oxidative stress mediated idiosyncratic drug toxicity. Drug Metab Rev 37:311–325. https://doi.org/10.1081/dmr-55227

    Article  CAS  PubMed  Google Scholar 

  38. Cetiner M, Sener G, Sehirli AO et al (2005) Taurine protects against methotrexate-induced toxicity and inhibits leukocyte death. Toxicol Appl Pharmacol 209:39–50. https://doi.org/10.1016/j.taap.2005.03.009

    Article  CAS  PubMed  Google Scholar 

  39. Dervieux T, Brenner TL, Hon YY et al (2002) De novo purine synthesis inhibition and antileukemic effects of mercaptopurine alone or in combination with methotrexate in vivo. Blood 15:1240–1247. https://doi.org/10.1182/blood-2002-02-0495

    Article  CAS  Google Scholar 

Download references

Funding

This study was funded by the Karadeniz Technical University.

Author information

Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, Dr Sami Ulus Maternity and Children Research and Training Hospital, 06080, Ankara, Turkey

    Nilgun Eroglu

  2. Department of Pediatric Hematology and Oncology, Karadeniz Technical University, Trabzon, Turkey

    Erol Erduran, Gokce Pinar Reis & Aysenur Bahadır

Authors
  1. Nilgun Eroglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Erol Erduran
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gokce Pinar Reis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aysenur Bahadır
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nilgun Eroglu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Eroglu, N., Erduran, E., Reis, G.P. et al. Therapeutic effect of N-acetylcysteine on chemotherapy-induced liver injury. Ir J Med Sci 189, 1189–1194 (2020). https://doi.org/10.1007/s11845-020-02219-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11845-020-02219-1

Keywords

  • Chemotherapy
  • Liver Injury
  • N-acetylcysteine