The evaluation of the protective effect of ambroxol against acetaminophen-induced hepatorenal toxicity in rats

Serkan Sayıner; Sevgi Gençosman; Hüseyin Şah; Nurhayat Gülmez; Ahmet Özer Şehirli

The evaluation of the protective effect of ambroxol against acetaminophen-induced hepatorenal toxicity in rats

Abstract

Acetaminophen (APAP), widely used as an analgesic-antipyretic drug, can cause liver and kidney damage at high doses. This study explored the protective effects of a mucolytic agent and an antioxidant Ambroxol (AMB), against APAP-induced toxicity in rats. The experiment included four groups of Wistar albino rats each having 6 animals in both sexes: a control group, an AMB-only group (50 mg/kg orally), an APAP-only group (1000 mg/kg intraperitoneally), and a combination APAP+AMB group. Twenty-four hours following the administration of APAP administration, rats were sacrificed. Measurements of blood levels of liver enzymes (AST, ALT, ALP, LDH), kidney function markers (Urea, Creatinine), and antioxidant enzymes (SOD, GPx) were performed. GPx and SOD activities were also assessed in hepatic and renal tissue samples. Histological examination of hepatic and renal tissues was conducted using Haematoxylin and Eosin staining. Results showed that APAP significantly increased liver enzymes, BUN, and Creatinine levels, indicating hepatorenal damage. This was accompanied by a decrease in plasma GPx and SOD activities. However, AMB treatment significantly mitigated these changes. It improved enzyme activities and increased hepatic GPx. Histologically, the APAP group showed liver cell damage, necrosis, haemorrhage, and inflammation, which were notably reduced in the AMB-treated group. This study suggests that Ambroxol effectively counters APAP- induced hepatorenal damage by restoring antioxidant enzyme levels and normalizing functional enzyme activities, highlighting its potential as a protective agent.

Keywords

References

[1] Wang X, Wu Q, Liu A, Anadón A, Rodríguez JL, Martínez-Larrañaga MR, Yuan Z, Martínez MA. Paracetamol: overdose-induced oxidative stress toxicity, metabolism, and protective effects of various compounds in vivo and in vitro. Drug Metab Rev. 49 (4): 395-437. https://doi.org/10.1080/03602532.2017.1354014
[2] Tittarelli R, Pellegrini M, Scarpellini MG, Marinelli E, Bruti V, Luca NM Di, Busardò FP, Zaami S. Hepatotoxicity of paracetamol and related fatalities. Eur Rev Med Pharmacol Sci. 2017; 21 (1): 95–101.
[3] Abdeen A, Abdelkader A, Abdo M, Wareth G, Aboubakr M, Aleya L, Abdel-Daim M. Protective effect of cinnamon against acetaminophen-mediated cellular damage and apoptosis in renal tissue. Environ Sci Pollut Res. 2019; 26 (1): 240–249. https://doi.org/10.1007/s11356-018-3553-2
[4] Wang Z, Hu JN, Yan MH, Xing JJ, Liu WC, Li W. Caspase-mediated anti-apoptotic effect of ginsenoside Rg5, a main rare ginsenoside, on acetaminophen-ınduced hepatotoxicity in mice. J Agric Food Chem. 2017; 65 (42): 9226–9236. https://doi.org/10.1021/acs.jafc.7b03361
[5] Murad HAS, Habib H, Kamel Y, Alsayed S, Shakweer M, Elshal M. Thearubigins protect against acetaminophen-induced hepatic and renal injury in mice: Biochemical, histopathological, immunohistochemical, and flow cytometry study. Drug Chem Toxicol. 2016; 39 (2): 190–198. https://doi.org/10.3109/01480545.2015.1070170
[6] Uzkeser M, Karakus E, Albayrak A, Kiki İ, Bayir Y, Cadirci E, Unal D, Halici Z, Karadeniz A. Protective effect of Panax ginseng against N-acetyl-p-aminophenol-induced hepatotoxicity in rats. Afr J Pharm Pharmacol. 2012; 6 (36): 2634–2642. https://doi.org/10.5897/AJPP12.658
[7] Jothy SL, Aziz A, Chen Y, Sasidharan S. Antioxidant activity and hepatoprotective potential of Polyalthia longifolia and Cassia spectabilis leaves against paracetamol-induced liver injury. Evid Based Complement Alternat Med. 2012;2012:561284. https://doi.org/10.1155/2012/561284
[8] Ghosh J, Das J, Manna P, Sil PC. Acetaminophen induced renal injury via oxidative stress and TNF-α production: Therapeutic potential of arjunolic acid. Toxicology. 2010; 268 (1-2): 8–18. https://doi.org/10.1016/j.tox.2009.11.011

[9] Ozatik FY, Teksen Y, Kadioglu E, Ozatik O, Bayat Z. Effects of hydrogen sulfide on acetaminophen-induced acute renal toxicity in rats. Int Urol Nephrol. 2019; 51 (4): 745–754. https://doi.org/10.1007/s11255-018-2053-0
[10] Mugford CA, Tarloff JB. The contribution of oxidation and deacetylation to acetaminophen nephrotoxicity in female Sprague-Dawley rats. Toxicol Lett. 1997; 93 (1): 15–22. https://doi.org/10.1016/S0378-4274(97)00063-5
[11] Isik B, Bayrak R, Akcay A, Sogut S. Erdosteine against acetaminophen induced renal toxicity. Mol Cell Biochem. 2006; 287 (1–2): 185–191. https://doi.org/10.1007/s11010-005-9110-6
[12] Azarmehr N, Afshar P, Moradi M, Sadeghi H, Sadeghi H, Alipoor B, Khalvati B, Barmoudeh Z, Abbaszadeh-Goudarzi K, Doustimotlagh AH. Hepatoprotective and antioxidant activity of watercress extract on acetaminophen-induced hepatotoxicity in rats. Heliyon. 2019; 5 (7): e02072. https://doi.org/10.1016/j.heliyon.2019.e02072
[13] Cazan D, Klimek L, Sperl A, Plomer M, Kölsch S. Safety of ambroxol in the treatment of airway diseases in adult patients. Expert Opin Drug Saf. 2018; 17 (12): 1211–1224. https://doi.org/10.1080/14740338.2018.1533954
[14] Sunkari S, Thatikonda S, Pooladanda V, Challa VS, Godugu C. Protective effects of ambroxol in psoriasis like skin inflammation: Exploration of possible mechanisms. Int Immunopharmacol. 2019; 71 301–312. https://doi.org/10.1016/j.intimp.2019.03.035
[15] Gültekin Ç, Sayiner S, Çetinel Ş, Şehirli AÖ. Does Ambroxol alleviate kidney ischemia-reperfusion injury in rats? Iran J Basic Med Sci. 2022; 25 (8): 1037–1041. https://doi.org/10.22038/IJBMS.2022.64330.14148
[16] Gultekin C, Sehirli AO, Cetinel S, Sayiner S. Could Ambroxol reduce cytokines in hepatic ischemia-reperfusion injury in rats? Bratisl Lek Listy. 2022; 123 (5): 381–384. https://doi.org/10.4149/BLL_2022_060
[17] Nowak D, Antczak A, Król M, Bialasiewicz P, Pietras T. Antioxidant properties of ambroxol. Free Radic Biol Med. 1994; 16 (4): 517–522. https://doi.org/10.1016/0891-5849(94)90130-9
[18] Zhi QM, Yang LT, Sun HC. Protective effect of ambroxol against paraquat-induced pulmonary fibrosis in rats. Intern Med. 2011; 50 (18): 1879–1887. https://doi.org/10.2169/internalmedicine.50.5407
[19] Fersahoğlu MM, Özkan E, Velioğlu-Öğünç A, Sayıner S, Ercan F, Çilingir Kaya ÖT, Şehirli AÖ. Impact of pycnogenol on acetaminophen-ınduced hepatorenal damage. Biointerface Res Appl Chem. 2022; 12 (6): 8070–8080. https://doi.org/10.33263/BRIAC126.80708080
[20] Sener G, Omurtag GZ, Sehirli O, Tozan A, Yüksel M, Ercan F, Gedik N. Protective effects of Ginkgo biloba against acetaminophen-induced toxicity in mice. Mol Cell Biochem. 2006; 283 (1–2): 39–45. https://doi.org/10.1007/s11010-006-2268-8
[21] Sener G, Sehirli O, Cetinel S, Yeğen BG, Gedik N, Ayanoğlu-Dülger G. Protective effects of MESNA (2-mercaptoethane sulphonate) against acetaminophen-induced hepatorenal oxidative damage in mice. J Appl Toxicol. 2005; 25 (1): 20–29. https://doi.org/10.1002/jat.1012
[22] Li J, Gao Y, Cui L, He H, Zheng J, Mo S, Zhou X, Chu S, Sun X, Chen N, Wang H. Combination of monoammonium glycyrrhizinate and cysteine hydrochloride protects mice against acetaminophen-induced liver injury via Keap1/Nrf2/ARE pathway. J Pharm Pharmacol. 2022; 74 (5): 730–739. https://doi.org/10.1093/jpp/rgab180
[23] Wang K, Yang L, Zhou J, Pan X, He Z, Liu J, Zhang Y. Smilax china L. Polysaccharide Alleviates Oxidative Stress and Protects From Acetaminophen-Induced Hepatotoxicity via Activating the Nrf2-ARE Pathway. Front Pharmacol. 2022; 13 888560. https://doi.org/10.3389/fphar.2022.888560
[24] Dong K, Zhang M, Liu Y, Gao X, Wu X, Shi D, Guo C, Wang J. Pterostilbene-loaded soluplus/poloxamer 188 mixed micelles for protection against acetaminophen-ınduced acute liver ınjury. Mol Pharm. 2023; 20 (2): 1189–1201. https://doi.org/10.1021/acs.molpharmaceut.2c00881
[25] Hammad AM, Shawaqfeh B, Hikmat S, Al-Qirim T, Hamadneh L, Al-Kouz S, Awad MM, Hall FS. The role of vitamin e in protecting against oxidative stress, ınflammation, and the neurotoxic effects of acute paracetamol in pregnant female rats. Toxics. 2023; 11 (4): 368. https://doi.org/10.3390/toxics11040368
[26] Koç A, Gazi M, Caner Sayar A, Onk D, Ali Arı M, Süleyman B, Gökhan Ağgül A, Altındağ F, Altuner D, Süleyman H. Molecular mechanism of the protective effect of adenosine triphosphate against paracetamol-induced liver toxicity in rats. Gen Physiol Biophys. 2023; 42 (2): 201–208. https://doi.org/10.4149/gpb_2022055
[27] Gupta PR. Ambroxol hydrochloride in the management of idiopathic pulmonary fibrosis: Clinical trials are the need of the hour. Lung India. 2014; 31 (1): 43–46. https://doi.org/10.4103/0970-2113.125899
[28] Wang Y, Wang F-Y, Pan Z, Dai Y-Y, Xu H-J, Jin K-K, Wang W-T. Effects of ambroxol combined with low-dose heparin on TNF-alpha and IL-1beta in rabbits with acute lung injury. Chin J Appl Physiol. 2011; 27 (2): 231–235.
[29] Ebada ME. Essential oils of green cumin and chamomile partially protect against acute acetaminophen hepatotoxicity in rats. An Acad Bras Cienc. 2018; 90 (2 suppl 1): 2347–2358. https://doi.org/10.1590/0001-3765201820170825
[30] Ko J-W, Shin J-Y, Kim J-W, Park S-H, Shin N-R, Lee I-C, Shin I-S, Moon C, Kim S-H, Kim S-H, Kim J-C. Protective effects of diallyl disulfide against acetaminophen-induced nephrotoxicity: A possible role of CYP2E1 and NF-κB. Food Chem Toxicol. 2017; 102 156–165. https://doi.org/10.1016/j.fct.2017.02.021
[31] Reshi MS, Shrivastava S, Jaswal A, Sinha N, Uthra C, Shukla S. Gold nanoparticles ameliorate acetaminophen induced hepato-renal injury in rats. Exp Toxicol Pathol. 2017; 69 (4): 231–240. https://doi.org/10.1016/j.etp.2017.01.009
[32] Jiang K, Wang X, Mao X, Lao H, Zhang J, Wang G, Cao Y, Tong I, Zhang F. Ambroxol alleviates hepatic ıschemia reperfusion ınjury by antioxidant and antiapoptotic pathways. Transplant Proc. 2013; 45 (6): 2439–2445. https://doi.org/10.1016/j.transproceed.2013.04.007
[33] Elbe H, Gul M, Cetin A, Taslidere E, Ozyalin F, Turkoz Y, Otlu A. Resveratrol reduces light and electron microscopic changes in acetaminophen-induced hepatotoxicity in rats: Role of iNOS expression. Ultrastruct Pathol. 2018; 42(1): 39-48. https://doi.org/10.1080/01913123.2017.1374313
[34] Zhao SP, Guo QL, Wang RK, Wang E. Oxidative and anti-oxidative effects of ambroxol on acute hydrochloric acid-induced lung injury in rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2004; 29 (5): 586–588.
[35] Baluchamy S, Ravichandran P, Periyakaruppan A, Ramesh V, Hall JC, Zhang Y, Jejelowo O, Gridley DS, Wu H, Ramesh GT. Induction of cell death through alteration of oxidants and antioxidants in lung epithelial cells exposed to high energy protons. J Biol Chem. 2010; 285 (32): 24769–24774. https://doi.org/10.1074/jbc.M110.138099
[36] Ciftci O, Onat E, Cetin A. The beneficial effects of fish oil following cisplatin-ınduced oxidative and histological damage in liver of rats. Iran J Pharm Res. 2017; 16 (4): 1424–1431.
[37] Aykaç A, Şah H, Kükner A, Sayıner S, Şehirli AÖ. Effects of chitosan on cisplatin-ınduced hepatorenal toxicity in an animal model. Istanbul Med J. 2022; 23 (3): 183–188. https://doi.org/10.4274/imj.galenos.2022.54077
[38] Moneim LMA, Helmy MW, El-Abhar HS. Co-targeting of endothelin-A and vitamin D receptors: a novel strategy to ameliorate cisplatin-induced nephrotoxicity. Pharmacol Reports. 2019; 71 (5): 917–925. https://doi.org/10.1016/j.pharep.2019.04.018
[39] Şah H, Gülmez N, Söyler G, Sayıner S, Şehirli AÖ, Kükner A. Effect of kefir on ıncreased apoptosis in liver and kidney in cisplatin toxicity. Int J Morphol. 2022; 40 (2): 480–488.

Details

Primary Language

English

Subjects

Basic Pharmacology

Journal Section

Research Article

Authors

Serkan Sayıner ^*
0000-0002-3297-5369
Kuzey Kıbrıs Türk Cumhuriyeti

Sevgi Gençosman
0000-0003-1979-3058
Kuzey Kıbrıs Türk Cumhuriyeti

Hüseyin Şah
0000-0003-0480-1609
Kuzey Kıbrıs Türk Cumhuriyeti

Nurhayat Gülmez
0000-0003-1609-2598
Türkiye

Ahmet Özer Şehirli
0000-0002-5175-9290
Kuzey Kıbrıs Türk Cumhuriyeti

Publication Date

June 28, 2025

Submission Date

February 6, 2024

Acceptance Date

March 14, 2024

Published in Issue

Year 2024 Volume: 28 Number: 4

IZ

https://izlik.org/JA33NT62KU

Cite

RIS / Bibtex

APA

Sayıner, S., Gençosman, S., Şah, H., Gülmez, N., & Şehirli, A. Ö. (2025). The evaluation of the protective effect of ambroxol against acetaminophen-induced hepatorenal toxicity in rats. Journal of Research in Pharmacy, 28(4), 1210-1219. https://izlik.org/JA33NT62KU

AMA

1.Sayıner S, Gençosman S, Şah H, Gülmez N, Şehirli AÖ. The evaluation of the protective effect of ambroxol against acetaminophen-induced hepatorenal toxicity in rats. J. Res. Pharm. 2025;28(4):1210-1219. https://izlik.org/JA33NT62KU

Chicago

Sayıner, Serkan, Sevgi Gençosman, Hüseyin Şah, Nurhayat Gülmez, and Ahmet Özer Şehirli. 2025. “The Evaluation of the Protective Effect of Ambroxol Against Acetaminophen-Induced Hepatorenal Toxicity in Rats”. Journal of Research in Pharmacy 28 (4): 1210-19. https://izlik.org/JA33NT62KU.

EndNote

Sayıner S, Gençosman S, Şah H, Gülmez N, Şehirli AÖ (July 1, 2025) The evaluation of the protective effect of ambroxol against acetaminophen-induced hepatorenal toxicity in rats. Journal of Research in Pharmacy 28 4 1210–1219.

IEEE

[1]S. Sayıner, S. Gençosman, H. Şah, N. Gülmez, and A. Ö. Şehirli, “The evaluation of the protective effect of ambroxol against acetaminophen-induced hepatorenal toxicity in rats”, J. Res. Pharm., vol. 28, no. 4, pp. 1210–1219, July 2025, [Online]. Available: https://izlik.org/JA33NT62KU

ISNAD

Sayıner, Serkan - Gençosman, Sevgi - Şah, Hüseyin - Gülmez, Nurhayat - Şehirli, Ahmet Özer. “The Evaluation of the Protective Effect of Ambroxol Against Acetaminophen-Induced Hepatorenal Toxicity in Rats”. Journal of Research in Pharmacy 28/4 (July 1, 2025): 1210-1219. https://izlik.org/JA33NT62KU.

JAMA

1.Sayıner S, Gençosman S, Şah H, Gülmez N, Şehirli AÖ. The evaluation of the protective effect of ambroxol against acetaminophen-induced hepatorenal toxicity in rats. J. Res. Pharm. 2025;28:1210–1219.

MLA

Sayıner, Serkan, et al. “The Evaluation of the Protective Effect of Ambroxol Against Acetaminophen-Induced Hepatorenal Toxicity in Rats”. Journal of Research in Pharmacy, vol. 28, no. 4, July 2025, pp. 1210-9, https://izlik.org/JA33NT62KU.

Vancouver

1.Serkan Sayıner, Sevgi Gençosman, Hüseyin Şah, Nurhayat Gülmez, Ahmet Özer Şehirli. The evaluation of the protective effect of ambroxol against acetaminophen-induced hepatorenal toxicity in rats. J. Res. Pharm. [Internet]. 2025 Jul. 1;28(4):1210-9. Available from: https://izlik.org/JA33NT62KU