HEPATOPROTECTIVE EFFECTS OF TANNIC ACID AGAINST CADMIUM-INDUCED OXIDATIVE STRESS: A MECHANISTIC INSIGHT
DOI:
https://doi.org/10.22159/ajpcr.2026v19i4.57442Keywords:
Antioxidant, Cadmium, Liver, Oxidative Stress, Tannic AcidAbstract
Objectives: This study explores the potential hepatoprotective effects of tannic acid (TA), a polyphenolic antioxidant, in mitigating cadmium (Cd)-induced oxidative stress in male Wistar rats.
Methods: Cd was administered to induce oxidative stress-induced damage in male Wistar rats, and TA was orally fed to assess its protective role. Following the completion of the 15-day treatment period, serum organ damage markers, biomarkers of oxidative stress, activities of the Krebs’ cycle enzymes, and respiratory chain enzymes were measured. Alteration of glycogen and collagen content were histologically studied to evaluate the state of inflammation and tissue damage. Changes in mitochondrial morphology were also studied. In addition, the interaction of Cd with an important antioxidant enzyme, catalase (CAT), was also studied.
Results: Rats pre-treated with TA showed significant protection against the harmful alterations caused by Cd by reducing endogenous reactive oxygen species through the control of the antioxidant defense system, inflammatory responses, and metabolic enzyme activities. Moreover, TA was also found to protect the tissue morphology and collagen deposition of the hepatic tissue and mitochondrial morphology, possibly by increasing mitochondrial viability. From isothermal titration calorimetry and circular dichroism spectroscopy studies, it is evident that TA can protect the secondary structure of CAT from being altered in the presence of Cd.
Conclusion: Our results systematically demonstrate that TA provided protection against Cd-induced oxidative stress-mediated damage in rat liver tissues through its antioxidant and metal chelating mechanism(s). The results suggest the possibility of using TA alone or alongside dietary interventions in instances of oxidative stress triggered by Cd, emphasizing its potential therapeutic relevance.
Downloads
References
1. Genchi G, Sinicropi MS, Lauria G, Carocci A, Catalano A. The effects of cadmium toxicity. Int J Environ Res Public Health. 2020 May 26;17(11):3782. doi: 10.3390/ijerph17113782, PMID 32466586
2. El-Sheikh R, Hegazy I, Zaghlool E, Ali EA, Gouda AA. Hydrochemical characteristics and water quality assessment in Abu-Zaabal area, Eastern Nile Delta, Egypt. Int J Appl Pharm. 2021 Nov 7;13:221-31. 3. Balali-Mood M, Naseri K, Tahergorabi Z, Khazdair MR, Sadeghi M. Toxic mechanisms of five heavy metals: Mercury, lead, chromium, cadmium, and arsenic. Front Pharmacol. 2021 Apr 13;12:643972. doi: 10.3389/fphar.2021.643972, PMID 33927623
4. Bunu SJ, George D, Alfred-Ugbenbo D, Ebeshi BU. Heavy metals quantification and correlative carcinogenic-risks evaluation in selected energy drinks sold in Bayelsa State using atomic absorption spectroscopic technique. Int J Chem Res. 2023 Oct 1;7:1-4. doi: 10.22159/ijcr.2023v7i4.224
5. Tarakina NV, Verberck B. A portrait of cadmium. Nat Chem. 2016 Dec 20;9(1):96. doi: 10.1038/nchem.2699, PMID 27995910
6. Nordberg GF. Cadmium and health in the 21st century--historical remarks and trends for the future. BioMetals. 2004;17(5):485-9. doi: 10.1023/B: BIOM.0000045726.75367.85, PMID 15688851
7. Friberg L. Health hazards in the manufacture of alkaline accumulators with special reference to chronic cadmium poisoning; A clinical and experimental study. Acta Med Scand Suppl. 1950;240:1-124. PMID 15432153
8. Hong D, Min JY, Min KB. Association between cadmium exposure and liver function in adults in the United States: A cross-sectional study. J Prev Med Public Health. 2021 Nov 1;54(6):471-80. doi: 10.3961/ jpmph.21.435, PMID 34875830
9. Branca JJ, Morucci G, Pacini A. Cadmium-induced neurotoxicity: Still much ado. Neural Regen Res. 2018 Jan 1;13(11):1879-82. doi: 10.4103/1673-5374.239434, PMID 30233056
10. Xie D, Yan J, Zhang H, Zhang H, Nie G, Zhu X, et al. Cadmium exacerbates liver injury by remodeling ceramide metabolism: Multiomics and laboratory evidence. Sci Total Environ. 2024 May 1;923:171405. doi: 10.1016/j.scitotenv.2024.171405, PMID 38432385
11. Branca JJ, Fiorillo C, Carrino D, Paternostro F, Taddei N, Gulisano M, et al. Cadmium-induced oxidative stress: Focus on the central nervous system. Antioxidants (Basel). 2020 Jun 1;9(6):492. doi: 10.3390/ antiox9060492, PMID 32516892
12. Heyno E, Klose C, Krieger-Liszkay A. Origin of cadmium-induced reactive oxygen species production: Mitochondrial electron transfer versus plasma membrane NADPH oxidase. New Phytol. 2008;179(3):687-99. doi: 10.1111/j.1469-8137.2008.02512.x, PMID 18537884
13. Palma FR, Gantner BN, Sakiyama MJ, Kayzuka C, Shukla S, Lacchini R, et al. ROS production by mitochondria: Function or dysfunction? Oncogene. 2023 Dec 11;43(5):295-303. doi: 10.1038/ s41388-023-02907-z, PMID 38081963
14. Lin AJ, Zhang XH, Chen MM, Cao Q. Oxidative stress and DNA damages induced by cadmium accumulation. J Environ Sci (China). 2007;19:596-602.
15. Rafati Rahimzadeh M, Rafati Rahimzadeh M, Kazemi S, Moghadamnia AA. Cadmium toxicity and treatment: An update. Caspian J Intern Med. 2017;8(3):135-45. doi: 10.22088/cjim.8.3.135, PMID 28932363
16. Seely DM, Wu P, Mills EJ. EDTA chelation therapy for cardiovascular disease: A systematic review. BMC Cardiovasc Disord. 2005 Nov 1;5:32. doi: 10.1186/1471-2261-5-32, PMID 16262904
17. Tandon SK, Jain VK, Mathur AK. Effect of metal chelators on excretion and tissue levels of essential trace elements. Environ Res. 1984;35(1):237-45. doi: 10.1016/0013-9351(84)90132-4, PMID 6436015
18. Majumder R, Datta M, Banerjee A, Bandyopadhyay D, Chattopadhyay A. Melatonin protects against ketorolac induced gastric mucosal toxic injuries through molecular mechanism associated with the modulation of arylakylamine N-acetyltransferase (AANAT) activity. Chem Biol Interact. 2023 Sep 1;382:110611. doi: 10.1016/j.cbi.2023.110611, PMID 37348669
19. Wang M, Huang H, Wang L, Yin L, Yang H, Chen C, et al. Tannic acid attenuates intestinal oxidative damage by improving antioxidant capacity and intestinal barrier in weaned piglets and IPEC-J2 cells. Front Nutr. 2022 Nov 4;9:1012207. doi: 10.3389/fnut.2022.1012207, PMID 36407512
20. Smeriglio A, Barreca D, Bellocco E, Trombetta D. Proanthocyanidins and hydrolysable tannins: Occurrence, dietary intake and pharmacological effects. Br J Pharmacol. 2016;174(11):1244-62. doi: 10.1111/bph.13630, PMID 27646690
21. Mitra E, Ghosh A, Ghosh D, Firdaus S, Mukherjee D, Chattopadhyay A, et al. Ameliorative effect of aqueous curry leaf (Murraya koenigi) extract against cadmium induced oxidative stress in rat liver: Involvement of antioxidant mechanisms. Int J Pharm Pharm Sci. 2013 Jan 1;5:570-83.
22. Winiarska-Mieczan A, Kwiecień M, Bąkowski M, Krusiński R, Jachimowicz-Rogowska K, Demkowska-Kutrzepa M, et al. Tannic acid and tea prevents the accumulation of lead and cadmium in the lungs, heart and brain of adolescent Male Wistar Rats-possible therapeutic option. Animals (Basel). 2022 Oct 19;12(20):2838. doi: 10.3390/ ani12202838, PMID 36290224
23. Hlaing CB, Chariyakornkul A, Pilapong C, Punvittayagul C, Srichairatanakool S, Wongpoomchai R. Assessment of systemic toxicity, genotoxicity, and early phase hepatocarcinogenicity of iron (III)-tannic acid nanoparticles in rats. Nanomaterials (Basel). 2022 Mar 22;12(7):1040. doi: 10.3390/nano12071040, PMID 35407158
24. Li M, Liu P, Xue Y, Liang Y, Shi J, Han X, et al. Tannic acid attenuates hepatic oxidative stress, apoptosis and inflammation by activating the Keap1-Nrf2/ARE signaling pathway in arsenic trioxide-toxicated rats. Oncol Rep. 2020 Sep 11;44:2306-16. doi: 10.3892/or.2020.7764
25. Sharma M, Devi P, Kaushal S, Ul-Ahsan A, Mehra S, Budhwar M, et al. Cyto and genoprotective potential of tannic acid against cadmium and nickel co-exposure induced hepato-renal toxicity in BALB/c mice. Biol Trace Elem Res. 2024 Dec 23;202(12):5624-36. doi: 10.1007/s12011- 024-04117-4, PMID 38393487
26. Majumder R, Datta M, Banerjee A, Roy T, Bandyopadhyay A, Bandyopadhyay D, et al. Possible role of the mitochondrial pyruvate dehydrogenase in ketorolac mediated onset and progression of gastric ulcers in male Wistar rats: Protection by melatonin. Biochim Biophys Acta Mol Basis Dis. 2025 Aug 1;1871(6):167908. doi: 10.1016/j. bbadis.2025.167908, PMID 40381814
27. Roy SG, De P, Mukherjee D, Chander V, Konar A, Bandyopadhyay D, et al. Excess of glucocorticoid induces cardiac dysfunction via activating angiotensin II pathway. Cell Physiol Biochem. 2009 Jul 1;24(1-2):1-10. doi: 10.1159/000227803, PMID 19590187
28. Mitra E, Ghosh AK, Ghosh D, Mukherjee D, Chattopadhyay A, Dutta S, et al. Protective effect of aqueous Curry leaf (Murraya koenigii) extract against cadmium-induced oxidative stress in rat heart. Food Chem Toxicol. 2012 May;50(5):1340-53. doi: 10.1016/j.fct.2012.01.048, PMID 22342528
29. Vogel B, Siebert H, Hofmann U, Frantz S. Determination of collagen content within picrosirius red stained paraffin-embedded tissue sections using fluorescence microscopy. MethodsX. 2015;2:124-34. doi: 10.1016/j.mex.2015.02.007, PMID 26150980
30. Datta M, Majumder R, Banerjee A, Bandyopadhyay D, Chattopadhyay A. Melatonin protects against diclofenac induced oxidative stress mediated myocardial toxicity in rats: A mechanistic insight. Food Chem Toxicol. 2024 Aug 1;190:114813. doi: 10.1016/j. fct.2024.114813, PMID 38876380
31. Strittmatter CF. Studies on avian xanthine dehydrogenases. Properties and patterns of appearance during development. J Biol Chem. 1965 Jun 1;240(6):2557-64. doi: 10.1016/S0021-9258(18)97361-8
32. Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol. 1978;52:302-10. doi: 10.1016/s0076-6879(78)52032-6, PMID 672633
33. Levine RL, Williams JA, Stadtman ER, Shacter E. Carbonyl assays for determination of oxidatively modified proteins. Methods Enzymol. 1994;233:346-57. doi: 10.1016/s0076-6879(94)33040-9, PMID 8015469
34. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem. 1968;25(1):192-205. doi: 10.1016/0003-2697(68)90092-4, PMID 4973948
35. Hare JF, Ching E, Attardi G. Isolation, subunit composition, and site of synthesis of human cytochrome c oxidase. Biochemistry. 1980 May 13;19(10):2023-30. doi: 10.1021/bi00551a003, PMID 6246917
36. Mukherjee D, Roy SG, Bandyopadhyay A, Chattopadhyay A, Basu A, Mitra E, et al. Melatonin protects against isoproterenol-induced myocardial injury in the rat: Antioxidative mechanisms. J Pineal Res. 2010 Apr 8;48(3):251-62. doi: 10.1111/j.1600-079X.2010.00749.x, PMID 20210856
37. Babbs CF, Steiner MG. Detection and quantitation of hydroxyl radical using dimethyl sulfoxide as molecular probe. Methods Enzymol. 1990;186:137-47. doi: 10.1016/0076-6879(90)86103-3, PMID 2172701
38. Marklund S, Marklund G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem. 1974 Sep 1;47(3):469-74. doi: 10.1111/ j.1432-1033.1974.tb03714.x, PMID 4215654
39. Beers RF Jr., Sizer IW. A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. J Biol Chem. 1952 Mar 1;195(1):133-40. doi: 10.1016/S0021-9258(19)50881-X, PMID 14938361
40. Krohne-Ehrich G, Schirmer RH, Untucht-Grau R. Glutathione reductase from human erythrocytes. Isolation of the enzyme and sequence analysis
of the redox-active peptide. Eur J Biochem. 1977 Oct 28;80(1):65-71. doi: 10.1111/j.1432-1033.1977.tb11856.x, PMID 923580
41. Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967 Jul;70(1):158-69. PMID 6066618
42. Greenlee L, Handler P. Xanthine oxidase. VI. Influence of pH on substrate specificity. J Biol Chem. 1964 Apr 1;239(4):1090-5. doi: 10.1016/S0021-9258(18)91395-5, PMID 14165912
43. Mukherjee D, Ghosh AK, Dutta M, Mitra E, Mallick S, Saha B, et al. Mechanisms of isoproterenol-induced cardiac mitochondrial damage: Protective actions of melatonin. J Pineal Res. 2015 Apr 23;58(3): 275-90. doi: 10.1111/jpi.12213, PMID 25652673
44. Chretien D, Pourrier M, Bourgeron T, Séné M, Rötig A, Munnich A, et al. An improved spectrophotometric assay of pyruvate dehydrogenase in lactate dehydrogenase contaminated mitochondrial preparations from human skeletal muscle. Clin Chim Acta. 1995 Sep 15;240(2):129-36. doi: 10.1016/0009-8981(95)06145-6, PMID 8548923
45. Duncan MJ, Fraenkel DG. Alpha-ketoglutarate dehydrogenase mutant of Rhizobium meliloti. J Bacteriol. 1979 Jan;137(1):415-9. doi: 10.1128/ jb.137.1.415-419.1979, PMID 762018
46. Veeger C, DerVartanian DV, Zeylemaker WP. [16] Succinate dehydrogenase: [EC 1.3.99.1 succinate: (Acceptor) oxidoreductase]. Methods Enzymol. 1969 Jan 1;13(C):81-90.
47. Mehler AH, Kornberg A. The enzymatic mechanism of oxidation-reductions between malate or isocitrate and pyruvate. J Biol Chem. 1948 Jul;174(3):961-77. doi: 10.1016/S0021-9258(18)57306-3, PMID 18871256
48. Abdel-Hamid NM, Ramadan MF, Amgad SW. Glycoregulatory enzymes as early diagnostic markers during premalignant stage in hepatocellular carcinoma. Am J Cancer Prev. 2013 May 20;1(2):14-9. doi: 10.12691/ajcp-1-2-1
49. Layzer RB, Rowland LP, Bank WJ. Physical and kinetic properties of human phosphofructokinase from skeletal muscle and erythrocytes. J Biol Chem. 1969 Jul 25;244(14):3823-31. doi: 10.1016/S0021- 9258(17)36424-4, PMID 4241008
50. Noltmann EA, Gubler CJ, Kuby SA. Glucose 6-phosphate dehydrogenase (Zwischenferment). I. Isolation of the crystalline enzyme from yeast. J Biol Chem. 1961 May 1;236(5):1225-30. doi: 10.1016/S0021-9258(18)64153-5, PMID 13729473
51. Goyal N, Srivastava VM. Oxidation and reduction of cytochrome c by mitochondrial enzymes of Setaria cervi. J Helminthol. 1995 Mar 5;69(1):13- 7. doi: 10.1017/S0022149X00013778, PMID 7622786
52. Bhogal RH, Curbishley SM, Weston CJ, Adams DH, Afford SC. Reactive oxygen species mediate human hepatocyte injury during hypoxia/reoxygenation. Liver Transpl. 2010 Nov;16(11):1303-13. doi: 10.1002/lt.22157, PMID 21031546
53. Obsil T, Ghirlando R, Klein DC, Ganguly S, Dyda F. Crystal structure of the 14-3-3zeta: Serotonin N-acetyltransferase complex. A role for scaffolding in enzyme regulation Cell. 2001 Apr;105(2):257-67. doi: 10.1016/S0092-8674(01)00316-6, PMID 11336675
54. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov 1;193(1): 265-75. doi: 10.1016/S0021-9258(19)52451-6
55. Majumder R, Datta M, Pal PK, Bhattacharjee B, Chattopadhyay A, Bandyopadhyay D. Protective mechanisms of melatonin on caprine spleen injury induced by cadmium (Cd): An in vitro study. Melatonin Res. 2019;2(3):57-75.
56. Bandyopadhyay D, Chatterjee AK, Datta AG. Effect of cadmium on purified hepatic flavokinase: Involvement of reactive -SH group(s) in the inactivation of flavokinase by cadmium. Life Sci. 1997 Apr 18;60(21):1891-903. doi: 10.1016/S0024-3205(97)00151-3, PMID 9155000
57. Mladenovic D, Radosavljevic T, Ninkovic M, Vucevic D, Sljivancanin T, Grbatinic I et al. Possible role of oxidative stress in acute cadmium hepatotoxicity in rats. Acta Vet Brno. 2010; 60(5-6):449-59. doi: 10.2298/AVB1006449M
58. Yiin SJ, Chern CL, Sheu JY, Lin TH. Cadmium-induced liver, heart, and spleen lipid peroxidation in rats and protection by selenium. Biol Trace Elem Res. 2000 Dec 1;78(1-3):219-30. doi: 10.1385/BTER:78:1- 3:219, PMID 11314980
59. El-Maraghy SA, Gad MZ, Fahim AT, Hamdy MA. Effect of cadmium and aluminum intake on the antioxidant status and lipid peroxidation in rat tissues. J Biochem Mol Toxicol. 2001 Jul 30;15(4):207-14. doi: 10.1002/jbt.18, PMID 11673849
60. Vollmar B, Menger MD. The hepatic microcirculation: Mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev. 2009 Oct;89(4):1269-339. doi: 10.1152/physrev.00027.2008, PMID 19789382
Published
How to Cite
Issue
Section
Copyright (c) 2026 Debasish Bandyopadhyay, Krishnendu Dalui, Adrita Banerjee, Romit Majumder, Madhuri Datta, Sanatan Mishra, Aindrila Chattopadhyay
This work is licensed under a Creative Commons Attribution 4.0 International License.
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.