Glycyrrhizic acid and the aqueous extract of Glycyrrhiza glabra attenuate hepatotoxicity in mice

Document Type : Original Article


1 Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

2 Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

3 Department of Life Sciences, Shanxi Agricultural University, Taigu, Shanxi, China

4 Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran


The liver injury could be induced in the association of a wide range of etiologies. Therefore, finding hepatoprotective agents with the potential clinical application has great value. Glycyrrhiza glabra (GG) is widely used in traditional medicine. The natural habitats of this plant are abundantly found in Iran. Besides, this plant could be cultivated on an industrial scale. The current study was designed to evaluate and compare the hepatoprotective effects of GG aqueous extract in two animal models. Moreover, the effect of GG extract was compared with glycyrrhizic acid (GHZA) as one of its most abundant components. Mice were treated with APAP (800 mg/kg, i.p) and CCl4 (0.8 ml/kg, in olive oil, i.p) as hepatotoxicants. Then, animals were treated with GG (150, 300, and 600 mg/kg, oral) and GHZA (30 mg/kg, oral). Moreover, animals were pre-treated with GG (600 mg/kg, seven consecutive days) before hepatotoxicity induction. A significant increase in serum biomarkers of liver injury and liver histopathological alterations were detected in APAP and CCl4-treated animals. Moreover, significant glutathione depletion and lipid peroxidation were evident in the liver of hepatotoxin-treated mice. It was found that GG water extract and GHZA significantly alleviated APAP and CCl4-induced liver injury. However, the effects of GG extract pre-treatment were more significant in comparison with post-treatment groups. Moreover, GG extract had a more significant hepatoprotective effect in comparison with GHZA. The effects of GG extract and GHZA on oxidative stress parameters seem to play a fundamental role in its hepatoprotective properties.


1. Friedman LS, Keeffe EB. Handbook of Liver Disease. London: Elsevier Health Sciences; 2011 2011/08/03/. 536 p.
2. Kaplowitz N. Drug-Induced Liver Disease: CRC Press; 2002 2002/10/16/. 790 p.
3. Niknahad H, Jamshidzadeh A, Heidari R,
Abdoli N, OmmatiMM,Jafari F, et al. The postulated hepatotoxic metabolite of methimazole causes mitochondrial dysfunction and energy metabolism disturbances in liver. Pharm Sci. 2016;22;217-26.
4. Najafi N, Jamshidzadeh A, Fallahzadeh H, Omidi M, Abdoli N, Najibi A, et al. Valproic acid-induced hepatotoxicity and the protective role of thiol reductants. Trend Pharm Sci. 2017;3;63-70.
5. Heidari R, Mohammadi H, Ghanbarinejad V, Ahmadi A, Ommati MM, Niknahad H, et al. Proline supplementation mitigates the early stage of liver injury in bile duct ligated rats. J Basic Clin Physiol Pharmacol. 2018 Dec 19;30(1):91-101. doi: 10.1515/jbcpp-2017-0221. PMID: 30205645.
6. Niknahad H, Heidari R, Alzuhairi AM, Najibi A. Mitochondrial dysfunction as a mechanism for pioglitazone-induced injury toward HepG2 cell line. Pharm Sci. 2015;20;169-74.
7. Heidari R, Niknahad H, Jamshidzadeh A, Abdoli N. Factors affecting drug-induced liver injury: antithyroid drugs as instances. Clin Mol Hepatol. 2014;20(3):237-248. doi:10.3350/cmh.2014.20.3.237
8. Heidari R, Niknahad H, Jamshidzadeh A, Eghbal MA, Abdoli N. An overview on the proposed mechanisms of antithyroid drugs-induced liver injury. Adv Pharm Bull. 2015;5(1):1-11. doi:10.5681/apb.2015.001
9. Abdoli N, Heidari R, Azarmi Y, Eghbal MA. Mechanisms of the statins cytotoxicity in freshly isolated rat hepatocytes. J Biochem Mol Toxicol. 2013 Jun;27(6):287-94. doi: 10.1002/jbt.21485. Epub 2013 Apr 23. PMID: 23761184.
10. Niknahad H, Hosseini H, Gozashtegan F, Ebrahimi F, Azarpira N, Abdoli N, et al. The hepatoprotective role of thiol reductants against mitoxantrone-induced liver injury. Trend Pharm Sci. 2017;3;113-22.
11. Bhamidimarri KR, Schiff E. Drug-induced cholestasis. Clin Liver Dis. 2013 Nov;17(4):519-31, vii. doi: 10.1016/j.cld.2013.07.015. PMID: 24099015.
12. Yoon E, Babar A, Choudhary M, Kutner M, Pyrsopoulos N. Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update. J Clin Transl Hepatol. 2016 Jun 28;4(2):131-42. doi: 10.14218/JCTH.2015.00052. Epub 2016 Jun 15. PMID: 27350943; PMCID: PMC4913076.
13. Heidari R, Arabnezhad MR, Ommati MM, Azarpira N, Ghodsimanesh E, Niknahad H. Boldine supplementation regulates mitochondrial function and oxidative stress in a rat model of hepatotoxicity. Pharma Sci. 2019;25;1-10. DOI: 10.15171/PS.2019.1
14. Heidari R, Babaei H, Eghbal MA. Cytoprotective Effects of Organosulfur Compounds against Methimazole Induced Toxicity in Isolated Rat Hepatocytes. Adv Pharm Bull. 2013;3(1):135-42. doi: 10.5681/apb.2013.023. Epub 2013 Feb 7. PMID: 24312826; PMCID: PMC3846059.
15. Heidari R, Niknahad H, Sadeghi A, Mohammadi H, Ghanbarinejad V, Ommati MM, et al. Betaine treatment protects liver through regulating mitochondrial function and counteracting oxidative stress in acute and chronic animal models of hepatic injury. Biomed Pharmacother. 2018 Jul;103:75-86. doi: 10.1016/j.biopha.2018.04.010. Epub 2018 Apr 7. PMID: 29635131.
6. Eghbal MA, Anoush M, Ghoreyshi A, Heidari R. The cytoprotective effects of Allium cepa methanolic extract in freshly isolated hepatocytes. Trend Pharm Sci. 2019;5;207-16.
17. Heidari R, Ahmadi F, Rahimi HR, Azarpira N, Hosseinzadeh M, Najibi A, et al. Exacerbated liver injury of antithyroid drugs in endotoxin-treated mice. Drug Chem Toxicol. 2019 Nov;42(6):615-623. doi: 10.1080/01480545.2018.1459668. Epub 2018 May 3. PMID: 29722569.
18. Dhama K, Karthik K, Khandia R, Munjal A, Tiwari R, Rana R, et al. Medicinal and Therapeutic Potential of Herbs and Plant Metabolites / Extracts Countering Viral Pathogens - Current Knowledge and Future Prospects. Curr Drug Metab. 2018;19(3):236-263. doi: 10.2174/1389200219666180129145252. PMID: 29380697.
19. Lee KW, Ching SM, Hoo FK, Ramachandran V, Swamy MK. Traditional medicinal plants and their therapeutic potential against major cancer types. In: Akhtar MS, Swamy MK, editors. Anticancer Plants: Natural Products and Biotechnological Implements: Volume 2. Singapore: Springer; 2018. p. 383-410.
20. Sharma P, Manchanda R, Goswami R, Chawla S. Biodiversity and therapeutic potential of medicinal plants. In: Shukla V, Kumar N, editors. Environmental Concerns and Sustainable Development: Volume 2: Biodiversity, Soil and Waste Management. Singapore: Springer; 2020. p. 27-44.
21. Ghafari S, Tavakoli Z, Shirooyeh P, Meybodi RN, Behmanesh E, Mokaberinejad R, et al. The Herbal Medicine Proposed by Iranian Traditional Medicine (Persian Medicine) for Treatment of Primary Dysmenorrhea: A Review. Trad Integr Med. 2018;30-42.
22. Jafarpour M, Yousefi G, Hamedi A. A Review of Herbal Medicine in Iranian Traditional Manuscripts for Treatment of Participatory Gastric Headache. Iran J Med Sci. 2016 May;41(3 Suppl):S17. PMID: 27840483; PMCID: PMC5103522.
23. Esmaeili H, Karami A, Hadian J, Nejad Ebrahimi S, Otto L-G. Genetic structure and variation in Iranian licorice (Glycyrrhiza glabra L.) populations based on morphological, phytochemical and simple sequence repeats markers. Ind Crops Prod. 2020;145;112140.
24. Sorkheh K, Zolfaghari M, Ercisli S. Reliability authentication of Glycyrrhiza glabra L. populations from south Iran using SSR and SNP-based markers. Proc Natl Acad Sci India Sect B Biol Sci. 2019;89;1283-94.
25. Khanahmadi M M, Naghdi Badi H, Akhondzadeh S, Khalighi – Sigaroodi F, Mehrafarin A, Shahriari S, Hajiaghaee R. A Review on Medicinal Plant of Glycyrrhiza glabra L. J Med Plant. 2013;12;1-12.
26. Hashem Dabaghian F, Kamalinejad M, Shojaii A, Abdollahi Fard M, Ghushegir SA. Review of antidiabetic plants in Iranian traditional medicine and their efficacy. J Med Plant. 2012;11;1-11.
27. Jafari Z, Emtiazy M, Sohrabvand F, Talei D, Oveidzadeh L, Abrishamkar M, Meyssami M, Kamalinejad M. The effect of Glycyrrhiza glabra L. on Primary Dysmenorrhea compared with Ibuprofen: A Randomized, Triple-Blind Controlled Trial. Iran J Pharm Res. 2019 Fall;18(Suppl1):291-301. doi: 10.22037/ijpr.2020.1100961. PMID: 32802108; PMCID: PMC7393041.
28. Ferrari P. Licorice: a sweet alternative to prevent hyperkalemia in dialysis patients? Kidney Int. 2009 Oct;76(8):811-2. doi: 10.1038/ki.2009.282. PMID: 19789539.
29. Gulati K, Rai N, Chaudhary S, Ray A. Chapter 6 - Nutraceuticals in Respiratory Disorders. In: Gupta RC, editor. Nutraceuticals. Boston: Academic Press; 2016. p. 75-86.
30. Hocaoglu AB, Karaman O, Erge DO, Erbil G, Yilmaz O, Bagriyanik A, Uzuner N. Glycyrrhizin and long-term histopathologic changes in a murine model of asthma. Curr Ther Res Clin Exp. 2011 Dec;72(6):250-61. doi: 10.1016/j.curtheres.2011.11.002. PMID: 24648593; PMCID: PMC3957157.
31. Samareh Fekri M, Poursalehi HR, Sharififar F, Mandegary A, Rostamzadeh F, Mahmoodi R. The effects of methanolic extract of Glycyrrhiza glabra on the prevention and treatment of bleomycin-induced pulmonary fibrosis in rat: experimental study. Drug Chem Toxicol. 2019 May 9:1-7. doi: 10.1080/01480545.2019.1606232. Epub ahead of print. PMID: 31072167.
32. Tanaka Y, Kikuzaki H, Fukuda S, Nakatani N. Antibacterial compounds of licorice against upper airway respiratory tract pathogens. J Nutr Sci Vitaminol (Tokyo). 2001 Jun;47(3):270-3. doi: 10.3177/jnsv.47.270. PMID: 11575586.
33. Chauhan P, Sharma H, Kumar U, Mayachari A, Sangli G, Singh S. Protective effects of Glycyrrhiza glabra supplementation against methotrexate-induced hepato-renal damage in rats: An experimental approach. J Ethnopharmacol. 2020 Dec 5;263:113209. doi: 10.1016/j.jep.2020.113209. Epub 2020 Jul 30. PMID: 32738390.
34. Eghlima G, Kheiry A, Sanikhani M, Hadian J, Aelaei M, Nejad Ebrahimi S. Investigation of phytochemical variability, antioxidant activity and ecological conditions of native Iranian Glycyrrhiza glabra L. Int J Horticult Sci Technol. 2020;7;387-400.
35. Jung JC, Lee YH, Kim SH, et al. Hepatoprotective effect of licorice, the root of Glycyrrhiza uralensis Fischer, in alcohol-induced fatty liver disease. BMC Complement Altern Med. 2016;16:19. Published 2016 Jan 22. doi:10.1186/s12906-016-0997-0
36. Abo El-Magd NF, El-Karef A, El-Shishtawy MM, Eissa LA. Hepatoprotective effects of glycyrrhizin and omega-3 fatty acids on Nuclear Factor-kappa B pathway in thioacetamide-induced fibrosis in rats. Egypt J Basic Appl Sci. 2015;2;65-74.
37. Chigurupati H, Auddy B, Biyani M, Stohs SJ. Hepatoprotective Effects of a Proprietary Glycyrrhizin Product during Alcohol Consumption: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study. Phytother Res. 2016 Dec;30(12):1943-1953. doi: 10.1002/ptr.5699. Epub 2016 Aug 19. PMID: 27539273.
38. Ommati MM, Jamshidzadeh A, Niknahad H, Mohammadi H, Sabouri S, Heidari R, Abdoli N. N-acetylcysteine treatment blunts liver failure-associated impairment of locomotor activity. PharmaNutrition. 2017;5;141-7.
39. Farshad O, Heidari R, Mohammadi H, Akbarizadeh AR, Zarshenas MM. Hepatoprotective Effects of Avicennia Marina (Forssk.) Vierh. Trend Pharm Sci. 2017;3;255-66.
40. Mobasher MA, Jamshidzadeh A, Heidari R, Ghahiri G, Mobasher N. Hepatoprotective effects of Artemia salina L. extract against carbon tetrachloride-induced toxicity. Trend Pharm Sci. 2016;2;259-64.
41. Niknahad H, Heidari R, Mokhtebaz T, Mansouri S, Dehshahri S, Abdoli N, Najibi A. Evaluating the effects of different fractions obtained from Gundelia tournefortii extract against carbon tetrachloride-induced liver injury in rats. Trend Pharm Sci. 2016;2;25-34.
42. Jamshidzadeh A, Heidari R, Razmjou M, Karimi F, Moein MR, Farshad O, Akbarizadeh AR, Shayesteh MR. An in vivo and in vitro investigation on hepatoprotective effects of Pimpinella anisum seed essential oil and extracts against carbon tetrachloride-induced toxicity. Iran J Basic Med Sci. 2015 Feb;18(2):205-11. PMID: 25825639; PMCID: PMC4366734.
43. Heidari R, Babaei H, Eghbal MA. Amodiaquine-induced toxicity in isolated rat hepatocytes and the cytoprotective effects of taurine and/or N-acetyl cysteine. Res Pharm Sci. 2014 Mar-Apr;9(2):97-105. PMID: 25657778; PMCID: PMC4311296.
44. Heidari R, Babaei H, Eghbal MA. Cytoprotective Effects of Organosulfur Compounds against Methimazole Induced Toxicity in Isolated Rat Hepatocytes. Adv Pharm Bull. 2013;3(1):135-42. doi: 10.5681/apb.2013.023. Epub 2013 Feb 7. PMID: 24312826; PMCID: PMC3846059.
45. Jamshidzadeh A, Heidari R, Abazari F, Ramezani M, Khodaei F, Ommati MM, Ayarzadeh M, Firuzi R, Saeedi A, Azarpira N, Najibi A. Antimalarial drugs-induced hepatic injury in rats and the protective role of carnosine. Pharm Sci. 2016;22;170-80.
46. Ommati MM, Farshad O, Azarpira N, Shafaghat M, Niknahad H, Heidari R. Betaine alleviates cholestasis-associated renal injury by mitigating oxidative stress and enhancing mitochondrial function. Biologia. 2021;76;351-65.
47. Jamshidzadeh A, Abdoli N, Niknahad H, Azarpira N, Mardani E, Mousavi S, Abasvali M, Heidari R. Taurine alleviates brain tissue markers of oxidative stress in a rat model of hepatic encephalopathy. Trend Pharm Sci. 2017;3;181-92.
48. Heidari R, Moezi L, Asadi B, Ommati MM, Azarpira N. Hepatoprotective effect of boldine in a bile duct ligated rat model of cholestasis/cirrhosis. PharmaNutrition. 2017;5;109-17.
49. Heidari R, Niknahad H, Jamshidzadeh A, Azarpira N, Bazyari M, Najibi A. Carbonyl traps as potential protective agents against methimazole-induced liver injury. J Biochem Mol Toxicol. 2015 Apr;29(4):173-81. doi: 10.1002/jbt.21682. Epub 2014 Dec 24. Erratum in: J Biochem Mol Toxicol. 2015 Aug;29(8):398. Dosage error in article text. PMID: 25545158.
50. Shafiekhani M, Ommati MM, Azarpira N, Heidari R, Salarian AA. Glycine supplementation mitigates lead-induced renal injury in mice. J Exp Pharmacol. 2019;11:15-22. Published 2019 Feb 18. doi:10.2147/JEP.S190846
51. Heidari R, Sadeghi N, Azarpira N, Niknahad H. Sulfasalazine-induced hepatic injury in an ex vivo model of isolated perfused rat liver and the protective role of taurine. Pharm Sci. 2015;21;211-9.
52. Heidari R, Behnamrad S, Khodami Z, Ommati MM, Azarpira N, Vazin A. The nephroprotective properties of taurine in colistin-treated mice is mediated through the regulation of mitochondrial function and mitigation of oxidative stress. Biomed Pharmacother. 2019 Jan;109:103-111. doi: 10.1016/j.biopha.2018.10.093. Epub 2018 Nov 2. PMID: 30396066.
53. Ommati MM, Farshad O, Ghanbarinejad V, Mohammadi HR, Khadijeh M, Negar A, et al. The Nephroprotective Role of Carnosine Against Ifosfamide-Induced Renal Injury and Electrolytes Imbalance is Mediated Via the Regulation of Mitochondrial Function and Alleviation of Oxidative Stress. Drug Res (Stuttg). 2020 Jan;70(1):49-56. doi: 10.1055/a-1017-5085. Epub 2019 Oct 31. PMID: 31671464.
54. Heidari R, Jamshidzadeh A, Niknahad H, Mardani E, Ommati MM, Azarpira N, et al. Effect of taurine on chronic and acute liver injury: Focus on blood and brain ammonia. Toxicol Rep. 2016 Apr 13;3:870-879. doi: 10.1016/j.toxrep.2016.04.002. PMID: 28959615; PMCID: PMC5615919.
55. Heidari R, Babaei H, Roshangar L, Eghbal MA. Effects of Enzyme Induction and/or Glutathione Depletion on Methimazole-Induced Hepatotoxicity in Mice and the Protective Role of N-Acetylcysteine. Adv Pharm Bull. 2014;4(1):21-8. doi: 10.5681/apb.2014.004. Epub 2013 Dec 23. PMID: 24409405; PMCID: PMC3885364.
56. Heidari R, Niknahad H. The Role and Study of Mitochondrial Impairment and Oxidative Stress in Cholestasis. In: Vinken M, editor. Experimental Cholestasis Research. Methods in Molecular Biology. New York, NY: Springer; 2019. p. 117-32.
57. Ommati MM, Jamshidzadeh A, Heidari R, Sun Z, Zamiri MJ, Khodaei F, et al. Carnosine and Histidine Supplementation Blunt Lead-Induced Reproductive Toxicity through Antioxidative and Mitochondria-Dependent Mechanisms. Biol Trace Elem Res. 2019 Jan;187(1):151-162. doi: 10.1007/s12011-018-1358-2. Epub 2018 May 16. PMID: 29767280.
58. Jamshidzadeh A, Heidari R, Mohammadi-Samani S, Azarpira N, Najbi A, Jahani P, et al. A comparison between the nephrotoxic profile of gentamicin and gentamicin nanoparticles in mice. J Biochem Mol Toxicol. 2015 Feb;29(2):57-62. doi: 10.1002/jbt.21667. Epub 2014 Oct 8. PMID: 25293820.
59. Heidari R, Esmailie N, Azarpira N, Najibi A, Niknahad H. Effect of Thiol-reducing Agents and Antioxidants on Sulfasalazine-induced Hepatic Injury in Normotermic Recirculating Isolated Perfused Rat Liver. Toxicol Res. 2016 Apr;32(2):133-40. doi: 10.5487/TR.2016.32.2.133. Epub 2016 Apr 30. PMID: 27123164; PMCID: PMC4843982.
60. Vazin A, Heidari R, Khodami Z. Curcumin Supplementation Alleviates Polymyxin E-Induced Nephrotoxicity. J Exp Pharmacol. 2020;12:129-136. Published 2020 Jun 4. doi:10.2147/JEP.S255861
61. Ommati MM, Niknahad H, Farshad O, Azarpira N, Heidari R. In Vitro and In Vivo Evidence on the Role of Mitochondrial Impairment as a Mechanism of Lithium-Induced Nephrotoxicity. Biol Trace Elem Res. 2021 May;199(5):1908-1918. doi: 10.1007/s12011-020-02302-9. Epub 2020 Jul 25. Erratum in: Biol Trace Elem Res. 2021 Jun;199(6):2429. PMID: 32712907.
62. Ommati MM, Farshad O, Mousavi K, Jamshidzadeh A, Azmoon M, Heidari S, et al. Betaine supplementation mitigates intestinal damage and decreases serum bacterial endotoxin in cirrhotic rats. PharmaNutrition. 2020;12;100179.
63. Ommati MM, Farshad O, Niknahad H, Arabnezhad MR, Azarpira N, Mohammadi HR, et al. Cholestasis-associated reproductive toxicity in male and female rats: The fundamental role of mitochondrial impairment and oxidative stress. Toxicol Lett. 2019 Nov;316:60-72. doi: 10.1016/j.toxlet.2019.09.009. Epub 2019 Sep 11. PMID: 31520699.
64. Niknahad H, Heidari R, Firuzi R, Abazari F, Ramezani M, Azarpira N, et al. Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats. Adv Pharm Bull. 2016 Dec;6(4):617-625. doi: 10.15171/apb.2016.076. Epub 2016 Dec 22. PMID: 28101469; PMCID: PMC5241420.
65. Ommati MM, Attari H, Siavashpour A, Shafaghat M, Azarpira N, Ghaffari H, Moezi L, Heidari R. Mitigation of cholestasis-associated hepatic and renal injury by edaravone treatment: Evaluation of its effects on oxidative stress and mitochondrial function. Liver Res. 2020;In Press.
66. Heidari R, Jamshidzadeh A, Ghanbarinejad V, Ommati MM, Niknahad H. Taurine supplementation abates cirrhosis-associated locomotor dysfunction. Clin Exp Hepatol. 2018 Jun;4(2):72-82. doi: 10.5114/ceh.2018.75956. Epub 2018 May 25. PMID: 29904723; PMCID: PMC6000746.
67. Ommati MM, Farshad O, Mousavi K, Taghavi R, Farajvajari S, Azarpira N, et al. Agmatine alleviates hepatic and renal injury in a rat model of obstructive jaundice. PharmaNutrition. 2020;13;100212.
68. Heidari R, Taheri V, Rahimi HR, Shirazi Yeganeh B, Niknahad H, Najibi A. Sulfasalazine-induced renal injury in rats and the protective role of thiol-reductants. Ren Fail. 2016;38(1):137-41. doi: 10.3109/0886022X.2015.1096731. Epub 2015 Oct 19. PMID: 26479898.
69. Jamshidzadeh A, Heidari R, Abasvali M, Zarei M, Ommati MM, Abdoli N, et al. Taurine treatment preserves brain and liver mitochondrial function in a rat model of fulminant hepatic failure and hyperammonemia. Biomed Pharmacother. 2017 Feb;86:514-520. doi: 10.1016/j.biopha.2016.11.095. Epub 2016 Dec 23. PMID: 28024286.
70. Ghanbarinejad V, Jamshidzadeh A, Khalvati B, Farshad O, Li H, Shi X, et al. Apoptosis-inducing factor plays a role in the pathogenesis of hepatic and renal injury during cholestasis. Naunyn Schmiedebergs Arch Pharmacol. 2021 Feb 1. doi: 10.1007/s00210-020-02041-7. Epub ahead of print. PMID: 33527194.
71. Jamshidzadeh A, Abdoli N, Niknahad H, Azarpira N, Mousavi S, Mardani E, Abasvali M, Heidari R. Carnosine supplementation mitigates brain tissue markers of oxidative stress in a rat model of fulminant hepatic failure. Trend Pharm Sci. 2017;3;149-60.
72. Heidari R, Jafari F, Khodaei F, Shirazi Yeganeh B, Niknahad H. Mechanism of valproic acid-induced Fanconi syndrome involves mitochondrial dysfunction and oxidative stress in rat kidney. Nephrology (Carlton). 2018 Apr;23(4):351-361. doi: 10.1111/nep.13012. PMID: 28141910.
73. Heidari R, Babaei H, Eghbal M. Mechanisms of methimazole cytotoxicity in isolated rat
hepatocytes. Drug Chem Toxicol. 2013 Oct;36(4):
403-11. doi: 10.3109/01480545.2012.749272. Epub 2012 Dec 21. PMID: 23256569.
74. Heidari R, Jamshidzadeh A, Niknahad H, Safari F, Azizi H, Abdoli N, et al. The Hepatoprotection provided by taurine and glycine against antineoplastic drugs induced liver injury in an ex vivo model of normothermic recirculating isolated perfused rat liver. Trend Pharm Sci. 2016;2;59-76.
75. Heidari R, Ommati MM, Alahyari S, Azarpira N, Niknahad H. Amino acid-containing krebs-henseleit buffer protects rat liver in a long-term organ perfusion model. Pharm Sci. 2018;24;168-79.
76. Ommati MM, Farshad O, Azarpira N, Ghazanfari E, Niknahad H, Heidari R. Silymarin mitigates bile duct obstruction-induced cholemic nephropathy. Naunyn Schmiedebergs Arch Pharmacol. 2021 Feb 4. doi: 10.1007/s00210-020-02040-8. Epub ahead of print. PMID: 33538845.
77. Heidari R, Jamshidzadeh A, Keshavarz N, Azarpira N. Mitigation of methimazole-induced hepatic injury by taurine in mice. Sci Pharm. 2015;83;143-58.
78. Karamikhah R, Jamshidzadeh A, Azarpira N, Saeidi A, Heidari R. Propylthiouracil-induced liver injury in mice and the protective role of taurine. Pharm Sci. 2016;21;94-101.
79. Ommati MM, Amjadinia A, Mousavi K, Azarpira N, Jamshidzadeh A, Heidari R. N-acetyl cysteine treatment mitigates biomarkers of oxidative stress in different tissues of bile duct ligated rats. Stress (Amsterdam, Netherlands). 2021;24;213-28. DOI: 10.1080/10253890.2020.1777970
80. Heidari R, Babaei H, Eghbal MA. Cytoprotective effects of taurine against toxicity induced by isoniazid and hydrazine in isolated rat hepatocytes. Arh Hig Rada Toksikol. 2013 Jun;64(2):15-24. doi: 10.2478/10004-1254-64-2013-2297. PMID: 23819928.
81. Niknahad H, Jamshidzadeh A, Heidari R, Zarei M, Ommati MM. Ammonia-induced mitochondrial dysfunction and energy metabolism disturbances in isolated brain and liver mitochondria, and the effect of taurine administration: relevance to hepatic encephalopathy treatment. Clin Exp Hepatol. 2017 Sep;3(3):141-151. doi: 10.5114/ceh.2017.68833. Epub 2017 Jul 5. PMID: 29062904; PMCID: PMC5649485.
82. Jamshidzadeh A, Heidari R, Latifpour Z, Ommati MM, Abdoli N, Mousavi S, et al. Carnosine ameliorates liver fibrosis and hyperammonemia in cirrhotic rats. Clin Res Hepatol Gastroenterol. 2017 Sep;41(4):424-434. doi: 10.1016/j.clinre.2016.12.010. Epub 2017 Mar 7. PMID: 28283328.
83. Heidari R, Ghanbarinejad V, Mohammadi H, Ahmadi A, Ommati MM, Abdoli N, et al. Mitochondria protection as a mechanism underlying the hepatoprotective effects of glycine in cholestatic mice. Biomed Pharmacother. 2018 Jan;97:1086-1095. doi: 10.1016/j.biopha.2017.10.166. Epub 2017 Nov 10. PMID: 29136945.
84. Niknahad H, Jamshidzadeh A, Heidari R, Hosseini Z, Mobini K, Khodaei F, et al. Paradoxical effect of methimazole on liver mitochondria: In vitro and in vivo. Toxicol Lett. 2016 Sep 30;259:108-115. doi: 10.1016/j.toxlet.2016.08.003. Epub 2016 Aug 6. PMID: 27506418.
85. Akram J, Hossein N, Reza H, Maryam A, Forouzan K, Mohammad Reza A, Omid F. Propylthiouracil-induced mitochondrial dysfunction in liver and its relevance to drug-induced hepatotoxicity. Pharm Sci. 2017;23;95-102.
86. Ommati MM, Heidari R. Chapter 38 - Betaine, heavy metal protection, oxidative stress, and the liver. In: Patel VB, Preedy VR, editors. Toxicology. New York: Academic Press; 2021. p. 387-95.
87. Heidari R, Ahmadi A, Ommati MM, Niknahad H. Methylene blue improves mitochondrial function in the liver of cholestatic rats. Trend Pharm Sci. 2020;6;73-86.
88. Ommati MM, Heidari R. Chapter 37 - Amino acids ameliorate heavy metals-induced oxidative stress in male/female reproductive tissue. In: Patel VB, Preedy VR, editors. Toxicology. New York: Academic Press; 2021. p. 371-86.
89. Nafisi S, Heidari R, Ghaffarzadeh M, Ziaee M, Hamzeiy H, Garjani A, et al. Cytoprotective effects of silafibrate, a newly-synthesised siliconated derivative of clofibrate, against acetaminophen-induced toxicity in isolated rat hepatocytes. Arh Hig Rada Toksikol. 2014 Jun;65(2):169-78. doi: 10.2478/10004-1254-65-2014-2434. PMID: 24706421.
90. Eftekhari A, Heidari R, Ahmadian E, Eghbal MA. Cytoprotective properties of carnosine against isoniazid-induced toxicity in primary cultured rat hepatocytes. Pharm Sci. 2018;24;257-63.
91. Ommati MM, Mohammadi H, Mousavi K, Azarpira N, Farshad O, Dehghani R, Najibi A, Kamran S, Niknahad H, Heidari R. Metformin alleviates cholestasis-associated nephropathy through regulating oxidative stress and mitochondrial function. Liver Res. 2020, In Press.
92. Azarang A, Farshad O, Ommati MM, Jamshidzadeh A, Heidari R, Abootalebi SN, et al. Protective role of probiotic supplements in hepatic steatosis: A rat model study. BioMed Res Int. 2020;2020;e5487659.
93. Chin YW, Jung HA, Liu Y, Su BN, Castoro JA, Keller WJ, Pereira MA, Kinghorn AD. Anti-oxidant constituents of the roots and stolons of licorice (Glycyrrhiza glabra). J Agric Food Chem. 2007 Jun 13;55(12):4691-7. doi: 10.1021/jf0703553. Epub 2007 May 22. PMID: 17516657.
94. Copple IM, Dinkova-Kostova AT, Kensler TW, Liby KT, Wigley WC. NRF2 as an Emerging Therapeutic Target. Oxid Med Cell Longev. 2017;2017:8165458. doi:10.1155/2017/8165458
95. Turpaev KT. Keap1-Nrf2 signaling pathway: mechanisms of regulation and role in protection of cells against toxicity caused by xenobiotics and electrophiles. Biochemistry (Mosc). 2013 Feb;78(2):111-26. doi: 10.1134/S0006297913020016. PMID: 23581983.
96. Kong AN, Owuor E, Yu R, Hebbar V, Chen C, Hu R, et al. Induction of xenobiotic enzymes by the MAP kinase pathway and the antioxidant or electrophile response element (ARE/EpRE). Drug Metab Rev. 2001 Aug-Nov;33(3-4):255-71. doi: 10.1081/dmr-120000652. PMID: 11768769.
97. Mukherjee S, Ghosh S, Choudhury S, Adhikary A, Manna K, Dey S, et al. Pomegranate reverses methotrexate-induced oxidative stress and apoptosis in hepatocytes by modulating Nrf2-NF-κB pathways. J Nutr Biochem. 2013 Dec;24(12):2040-50. doi: 10.1016/j.jnutbio.2013.07.005. PMID: 24231097.
98. Martínez-Huélamo M, Rodríguez-Morató J, Boronat A, de la Torre R. Modulation of Nrf2 by Olive Oil and Wine Polyphenols and Neuroprotection. Antioxidants (Basel). 2017 Sep 26;6(4):73. doi: 10.3390/antiox6040073. PMID: 28954417; PMCID: PMC5745483.
99. Zhou Y, Jiang Z, Lu H, Xu Z, Tong R, Shi J, Jia G. Recent Advances of Natural Polyphenols Activators for Keap1-Nrf2 Signaling Pathway. Chem Biodivers. 2019 Nov;16(11):e1900400. doi: 10.1002/cbdv.201900400. Epub 2019 Oct 10. PMID: 31482617.
100. Chen S, Zou L, Li L, Wu T. The protective effect of glycyrrhetinic acid on carbon tetrachloride-induced chronic liver fibrosis in mice via upregulation of Nrf2. PLoS One. 2013;8(1):e53662. doi: 10.1371/journal.pone.0053662. Epub 2013 Jan 14. PMID: 23341968; PMCID: PMC3544925.
101. Wu CH, Chen AZ, Yen GC. Protective Effects of Glycyrrhizic Acid and 18β-Glycyrrhetinic Acid against Cisplatin-Induced Nephrotoxicity in BALB/c Mice. J Agric Food Chem. 2015 Feb 4;63(4):1200-1209. doi: 10.1021/jf505471a. Epub 2015 Jan 26. PMID: 25588318.
102. Gandhi NM, Maurya DK, Salvi V, Kapoor S, Mukherjee T, Nair CK. Radioprotection of DNA by glycyrrhizic acid through scavenging free radicals. J Radiat Res. 2004 Sep;45(3):461-8. doi: 10.1269/jrr.45.461. PMID: 15613793.
103. Størmer FC, Reistad R, Alexander J. Glycyrrhizic acid in liquorice--evaluation of health hazard. Food Chem Toxicol. 1993 Apr;31(4):303-12. doi: 10.1016/0278-6915(93)90080-i. PMID: 8386690.