Protective Effects of Viburnum opulus L. (Gilaburu) on Amiodarone-Induced Hepatorenal Toxicity in Rats

Abstract

Objective Amiodarone is a widely prescribed antiarrhythmic agent, yet hepatotoxic and nephrotoxic side effects frequently limit its clinical use. Viburnum opulus L. (Gilaburu), a fruit native to the Kayseri region of Türkiye, is notable for its antioxidative, antiproliferative, and anti-inflammatory properties. Its rich composition of organic acids, phenolic compounds, amino acids, and vitamins suggests potential protective effects against drug-induced organ injury. Material and Method This study investigated the structural and biochemical changes induced by amiodarone in rat liver and kidney tissues, as well as the potential protective effects of gilaburu. Thirty-two male Wistar rats (300–350 g) were randomly assigned to four groups: control, amiodarone, amiodarone plus gilaburu, and gilaburu. Amiodarone was administered intraperitoneally at 100 mg/kg/day for 10 days, while gilaburu fruit extract was given orally at 100 mg/kg/day. At the end of treatment, hepatic and renal tissues were analyzed histochemically and immunohistochemically, and serum biochemical parameters were assessed. Results Histological evaluation revealed pronounced hepatic and renal damage in the amiodarone group, which was markedly reduced in the combined treatment group. Immunohistochemical staining for tumor necrosis factor- alpha and inducible nitric oxide synthase showed significantly higher expression in the amiodarone group compared with the combined group (p < 0.05). Biochemical analyses, including total antioxidant status, total oxidant status, and oxidative stress index, supported these findings. Conclusion Gilaburu fruit extract demonstrated significant protective effects against amiodarone-induced hepatic and renal injury. These results highlight its potential as a natural antioxidant agent that may mitigate drug-induced organ toxicity.

Keywords

• Amiodarone
• Hepatic
• Renal
• Gilaburu (Viburnum opulus L.)

Supporting Institution

This study was supported by the Scientific Research Projects Unit of Süleyman Demirel University (SDU-BAP, Project no: TYL-2021-8335)

Project Number

TYL-2021-8335

Ethical Statement

The study was approved by the Local Ethical Committee of Experimental Animal Ethics of Süleyman Demirel University (SDU) and was performed entirely according to ethical rules (Protocol Number: 04/11 dated 11.06.2021).

References

1. 1. Vaughan WEM. A Classification of Antiarrhythmic Actions Reassessed After a Decade of New Drugs. The Journal of Clinical Pharmacology 1984;24(4):129–47. Doi: 10.1002/j.1552- 4604.1984.tb01822.x
2. 2. Abbott GW, Levi R. Antiarrhythmic Drugs. In: Hemmings HC, Egan TD. Pharmacology and Physiology for Anesthesia. Philadelphia: Elsevier; 2019. Doi:10.1016/B978-0-323-48110- 6.00027-2
3. 3. Harvey RD. Agents Used in Cardiac Arrhytmias. In: Bertram G. Katzung's Basic & Clinical Pharmacology 14th Edition. McGraw Hill; 2018. p:228–53. ISBN: 978-1-260-46330-9
4. 4. Ernawati DK, Stafford L, Hughes JD. Amiodarone‐induced pulmonary toxicity. Br J Clin Pharmacol. 2008;66(1):82–7. Doi: 10.1111/j.1365-2125.2008.03177.x
5. 5. Martino E, Bartalena L, Bogazzi F, Braverman LE. The Effects of Amiodarone on the Thyroid. Endocr Rev. 2001;22(2):240– 54. Doi: 10.1210/edrv.22.2.0427
6. 6. Turk U, Turk B, Yilmaz S, Tuncer E, Alioglu E, Dereli T. Amiodarone- induced multiorgan toxicity with ocular findings on confocal microscopy. Middle East Afr J Ophthalmol. 2015;22(2):258. Doi: 10.4103/0974-9233.154411
7. 7. Boyacı H, Çöteli E, Karataş F. Investigation of Amounts of Vitamin A, Vitamin E, Beta-carotene, Lycopene, Reduced and Oxidized Glutathione in Fruits of Viburnum opulus L. Erzincan University Journal of Science and Technology 2016;9(2):111–7. Doi: 10.18185/eufbed.59250
8. 8. Çam M. Determination of organic acids and phenolic compounds by high pressure liquid chromatography in gilaburu (Viburnum opulus) fruit juice consumed in Kayseri region, [Master’s thesis]. İzmir: Institute of Science; 2005.

9. 9. Kalyoncu İH, Ersoy N, Elidemir AY, Karalı ME. Some Physico- Chemical Characteristics and Mineral Contents of Gilaburu (Viburnum opulus L.) Fruits in Turkey. International Journal of Agricultural and Biosystems Engineering 2013;7(6):424–6. Doi: 10.5281/zenodo.1079484
10. 10. Kajszczak D, Zakłos-Szyda M, Podsędek A. Viburnum opulus L.—A Review of Phytochemistry and Biological Effects. Nutrients 2020;12(11):3398. Doi: 10.3390/nu12113398
11. 11. Polka D, Podsędek A, Koziołkiewicz M. Comparison of Chemical Composition and Antioxidant Capacity of Fruit, Flower and Bark of Viburnum opulus. Plant Foods for Human Nutrition 2019;74(3):436–42. Doi: 10.1007/s11130-019-00759-1
12. 12. Altun ML, Özbek H, Saltan Çitoğlu G, Sever Yılmaz B, Bayram I, Cengiz N. Hepatoprotective and Hypoglycemic Activities of Viburnum opulus L. Turk J Pharm Sci. 2010;7(1):35–48.
13. 13. Walaa IM, Eman MA. Attenuation of Amiodarone-induced Lung, Liver and Kidney Toxicity by Nitric Oxide Synthase Inhibitor, Aminoguanidine in Rats. European of Biomedical and Pharmaceutical Sciences 2019;6(6):22–31.
14. 14. Datta S, Waghray T, Torres M, Glusman S. Amiodarone Decreases Heat, Cold, and Mechanical Hyperalgesia in a Rat Model of Neuropathic Pain. Anesth Analg. 2004;98(1):178–84. Doi: 10.1213/01.ANE.0000093223.35824.23
15. 15. Sarıözkan S, Türk G, Eken A, Bayram LÇ, Baldemir A, Doğan G. Gilaburu (Viburnum opulus L.) fruit extract alleviates testis and sperm damages induced by taxane-based chemotherapeutics. Biomedicine & Pharmacotherapy. 2017;95:1284–94. Doi: 10.1016/j.biopha.2017.09.057
16. 16. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005;38(12):1103–11. Doi: 10.1016/j.clinbiochem.2005.08.008
17. 17. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem. 2004;37(4):277–85. Doi: 10.1016/j.clinbiochem.2003.11.015
18. 18. McNaughton L, Puttagunta L, Martinez-Cuesta MA, Kneteman N, Mayers I, Moqbel R, et al. Distribution of nitric oxide synthase in normal and cirrhotic human liver. Proceedings of the National Academy of Sciences. 2002;99(26):17161–6. Doi: 10.1073/pnas.0134112100
19. 19. Schemitt EG, Colares JR, Hartmann RM, Morgan-Martins MI, Marroni CA, Tuñón JM, Marroni NP. Effect of glutamine on oxidative stress and inflammation in a rat model of fulminant hepatic failure. Nutr Hosp. 2016;33(2):210–9
20. 20. Diesen DL, Kuo PC. Nitric Oxide and Redox Regulation in the Liver: Part I. General Considerations and Redox Biology in Hepatitis. Journal of Surgical Research 2010;162(1):95–109. Doi: 10.1016/j.jss.2009.09.019
21. 21. Liwag T, Wong K, Martinez E, Nguyen S. Acute Multi-Organ Toxicity During 24-Hour Dosing of Intravenous Amiodarone: A Case Report. Cureus 2022;14(5). Doi: 10.7759/cureus.25028
22. 22. Hashmi A, Keswani NR, Kim S, Graham DY. Hepatic Dysfunction in Patients Receiving Intravenous Amiodarone. South Med J. 2016;109(2):83–6. Doi: 10.14423/SMJ.0000000000000413
23. 23. Duineveld MD, Kers J, Vleming L-J. Case report of progressive renal dysfunction as a consequence of amiodarone-induced phospholipidosis. Eur Heart J Case Rep. 2023;7(9). Doi: 10.1093/ehjcr/ytad457
24. 24. Gülada BÖ, Cam ME, Yüksel M, Akakın D, Taşkın T, Emre G, et al. Gilaburu (Viburnum opulus L.) fruit extract has potential therapeutic and prophylactic role in a rat model of acetic acid-induced oxidant colonic damage. J Ethnopharmacol. 2024;322:117624. Doi: 10.1016/j.jep.2023.117624
25. 25. Ceylan D, Aksoy A, Ertekin T, Yay AH, Nisari M, Karatoprak GŞ, et al. The effects of gilaburu (Viburnum opulus) juice on experimentally induced Ehrlich ascites tumor in mice. J Cancer Res Ther. 2018;14(2):314–20. Doi: 10.4103/0973-1482.181173
26. 26. Kim G, Choi H, Lee H, Moon K, Oh JH, Lee J, et al. Increased hepatic acylcarnitines after oral administration of amiodarone in rats. Journal of Applied Toxicology. 2020;40(7):1004–13. Doi: 10.1002/jat.3960
27. 27. Sakr SA, El-Gamal EM. Effect of grapefruit juice on amiodarone induced nephrotoxicity in albino rats. Toxicol Ind Health. 2016;32(1):68–75. Doi: 10.1177/0748233713498443
28. 28. Morales AI, Barata JD, Bruges M, Arévalo MA, González de Buitrago JM, Palma P, et al. Acute Renal Toxic Effect of Amiodarone in Rats. Pharmacol Toxicol. 2003;92(1):39–42. Doi: 10.1034/j.1600-0773.2003.920107.x
29. 29. Shaikh-Nisar A, Downar E, Butany J. Amiodarone? An inhibitor of phospholipase activity: a comparative study of the inhibitory effects of amiodarone, chloroquine and chlorpromazine. Mol Cell Biochem. 1987;76(2). Doi: 10.1007/BF00223481
30. 30. Hinkovska-Galcheva V, Treadwell T, Shillingford JM, Lee A, Abe A, Tesmer JJG, et al. Inhibition of lysosomal phospholipase A2 predicts drug-induced phospholipidosis. J Lipid Res. 2021;62:100089. Doi: 10.1016/j.jlr.2021.100089
31. 31. Lenhard SC, Lev M, Webster LO, Peterson RA, Goulbourne CN, Miller RT, et al. Hepatic Phospholipidosis Is Associated with Altered Hepatobiliary Function as Assessed by Gadoxetate Dynamic Contrast–enhanced Magnetic Resonance Imaging. Toxicol Pathol. 2016;44(1):51–60. Doi: 10.1177/0192623315608509
32. 32. Gluck N, Fried M, Porat R. Acute amiodarone liver toxicity likely due to ischemic hepatitis. Isr Med Assoc J. 2011;13(12):748–52.
33. 33. Fonseca P. Acute hepatitis after amiodarone infusion. World J Clin Cases. 2015;3(10):900–3. Doi: 10.12998/wjcc.v3.i10.900
34. 34. Patel A, Hoffman E, Ball D, Klapwijk J, Steven RT, Dexter A, et al. Comparison of Oral, Intranasal and Aerosol Administration of Amiodarone in Rats as a Model of Pulmonary Phospholipidosis. Pharmaceutics 2019;11(7):345. Doi: 10.3390/pharmaceutics11070345
35. 35. Iwakiri Y, Kim MY. Nitric oxide in liver diseases. Trends Pharmacol Sci. 2015;36(8):524–36. Doi: 10.1016/j.tips.2015.05.001
36. 36. Rasheed R, Arsanyos S. Vitamin E Ameliorates the Toxic Effect of Amiodarone on Thyroid Gland in Rats: A Histological and Ultrastructural Study. Journal of Medical Histology. 2018;2(1):57– 68. Doi: 10.21608/jmh.2018.4614.1036
37. 37. Oka VO, Okon UE, Osim EE. Pulmonary Responses Following Quercetin Administration in Rats After Intratracheal Instillation of Amiodarone. Niger J Physiol Sci. 2019;34(1):63–8.
38. 38. Baş SS, Türkyılmaz I, Bolkent B, Yanardağ R. The influence of vitamin U supplementation on liver injury of amiodarone-administered rats. IUFS Journal of Biology. 2016;75(1):1–10.
39. 39. Eid RA, Zaki MSA, Al-Shraim M, Eldeen MA, Haidara MA. Grape seed extract protects against amiodarone - induced nephrotoxicity and ultrastructural alterations associated with the inhibition of biomarkers of inflammation and oxidative stress in rats. Ultrastruct Pathol. 2021;45(1):49–58. Doi: 10.1080/01913123.2020.1864076