Effects of quercetin on bisphenol A-induced mitochondrial toxicity in rat liver

Document Type : Original Article


1 Department of Toxicology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

3 Department of Clinical Pathology, School of Veterinary Medicine, University of Shahid Chamran, Ahvaz, Iran


Objective(s): Recognized as a distinguished environmental and global toxicant, Bisphenol A (BPA) affects the liver, which is a vital body organ, by the induction of oxidative stress. The present study was designed to investigate the protective effect of quercetin against BPA in hepatotoxicity in Wistar rats and also, the activity of mitochondrial enzymes were evaluated.
Materials and Methods: To this end, 32 male Wistar rats were divided into four groups (six rats per group), including control, BPA (250 mg/kg), BPA + quercetin (75 mg/kg), and quercetin (75 mg/kg).
Results: The BPA-induced alterations were restored in concentrations of alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) due to the quercetin treatment (75 mg/kg) (all P<0.001). While the levels of mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and malondialdehyde (MDA) decreased by the quercetin treatment in the liver mitochondria (P<0.001), Catalase (CAT) and glutathione (GSH) increased (P<0.001).
Conclusion: According to the results, the potential hepatotoxicity of BPA can be prevented by quercetin, which protects the body against oxidative stress and BPA-induced biochemical toxicity. Moreover, the reproductive toxicity of BPA after environmental or occupational exposures can be potentially prohibited by quercetin.


Main Subjects

1. Dodds EC, Lawson W. Synthetic strogenic agents without the phenanthrene nucleus. Nature 1936; 137:996.
2. Rudel RA, Gray JM, Engel CL, Rawsthorne TW, Dodson RE, Ackerman JM, et al. Food packaging and bisphenol A and bis (2-ethyhexyl) phthalate exposure: findings from a dietary intervention. Environ Health Perspec 2011; 119:914.
3. Halden RU. Plastics and health risks. Annual review of public health 2010; 31:179-194.
4. Carwile JL, Luu HT, Bassett LS, Driscoll DA, Yuan C, Chang JY, et al. Polycarbonate bottle use and urinary bisphenol A concentrations. Environ Health Perspec2009; 117:1368.
5. Vandenberg LN, Chahoud I, Heindel JJ, Padmanabhan V, Paumgartten FJ, Schoenfelder G. Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A. Environ Health Perspec 2010; 118:1055.
6. LaKind JS, Naiman DQ. Temporal trends in bisphenol A exposure in the United States from 2003–2012 and factors associated with BPA exposure: Spot samples and urine dilution complicate data interpretation. Environ Res 2015; 142:84-95.
7. Qin X-Y, Fukuda T, Yang L, Zaha H, Akanuma H, Zeng Q, et al. Effects of bisphenol A exposure on the proliferation and senescence of normal human mammary epithelial cells. Cancer Biol Ther 2012; 13:296-306.
8. Inoue H, Tsuruta A, Kudo S, Ishii T, Fukushima Y, Iwano H, et al. Bisphenol A glucuronidation and excretion in liver of pregnant and nonpregnant female rats. Drug Metab Dispos. 2004;33:55–59.
9. Grijalva J, Vakili K, editors. Neonatal liver physiology. Seminars in pediatric surgery; 2013: Elsevier.
10. Korkmaz A, Ahbab MA, Kolankaya D, Barlas N. Influence of vitamin C on bisphenol A, nonylphenol and octylphenol induced oxidative damages in liver of male rats. Environ Toxicol. 2009;26:325–337.
11. Izzotti A, Kanitz S, D’Agostini F, Camoirano A, De Flora S. Formation of adducts by bisphenol A, an endocrine disruptor, in DNA in vitro and in liver and mammary tissue of mice. Mutat Res 2009; 679:28-32.
12. Kourouma A, Quan C, Duan P, Qi S, Yu T, Wang Y, et al. Bisphenol A induces apoptosis in liver cells through induction of ROS. Adv Toxicol 2015; 2015. 10.1155/2015/901983.
13. Ahangarpour A, Alboghobeish S, Oroojan AA, Dehghani MA. Mice pancreatic islets protection from oxidative stress induced by single-walled carbon nanotubes through naringin. Hum Exp Toxicol 2018; 1:0960327118769704.
14. Videla LA. Oxidative stress signaling underlying liver disease and hepatoprotective mechanisms. World J Hepatol 2009 31;1:72-8.
15. Hassanpour SH, Dehghani MA, Karami SZ. Study of respiratory chain dysfunction in heart disease. J Cardiovasc Thorac Res 2018; 10:1-13.
16.Anjum S, Rahman S, Kaur M, Ahmad F, Rashid H, Ansari RA, et al. Melatonin ameliorates bisphenol A-induced biochemical toxicity in testicular mitochondria of mouse. Food Chem Toxicol 2011; 49:2849-2854.
17. Song B-J, Akbar M, Abdelmegeed MA, Byun K, Lee B, Yoon SK, et al. Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications. Redox Biol 2014; 3:109-123.
18. Ooe H, Taira T, Iguchi-Ariga SM, Ariga H. Induction of reactive oxygen species by bisphenol A and abrogation of bisphenol A-induced cell injury by DJ-1. Toxicol Sci 2005; 88:114-126.
19. Apostolova N, Gomez‐Sucerquia LJ, Moran A, Alvarez A, Blas‐Garcia A, Esplugues J. Enhanced oxidative stress and increased mitochondrial mass during efavirenz‐induced apoptosis in human hepatic cells. Br J Pharmacol 2010; 160:2069-2084.
20. Panieri E, Santoro MM. ROS signaling and redox biology in endothelial cells. Cell Mol Life Sci 2015; 72:3281-3303.
21. Naik E, Dixit VM. Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J Exp Med 2011; 208:417-420.
22. Khan S, Beigh S, Chaudhari BP, Sharma S, Aliul Hasan Abdi S, Ahmad S, et al. Mitochondrial dysfunction induced by Bisphenol A is a factor of its hepatotoxicity in rats. Environ Toxicol 2016; 31:1922-1934.
23. Gülçin İ, Topal F, Çakmakçı R, Bilsel M, Gören AC, Erdogan U. Pomological features, nutritional quality, polyphenol content analysis, and antioxidant properties of domesticated and 3 wild ecotype forms of raspberries (Rubus idaeus L.). J Food Sci 2011; 76:C585-C593.
24. Fraga CG, Galleano M, Verstraeten SV, Oteiza PI. Basic biochemical mechanisms behind the health benefits of polyphenols. Mol Aspects Med 2010; 31:435-445.
25. Zou W, Liu W, Yang B, Wu L, Yang J, Zou T, et al. Quercetin protects against perfluorooctanoic acid-induced liver injury by attenuating oxidative stress and inflammatory response in mice. Int Immunopharmacol 2015; 28:129-135.
26. Inal ME, Kahraman A. The protective effect of flavonol quercetin against ultraviolet A induced oxidative stress in rats1. Toxicology 2000; 154:21-29.
27. Olayinka ET, Ore A, Ola OS, Adeyemo OA. Protective effect of quercetin on melphalan-induced oxidative stress and impaired renal and hepatic functions in rat. Chemother Res Pract 2014; 2014.
28. Knekt P, Kumpulainen J, Järvinen R, Rissanen H, Heliövaara M, Reunanen A, et al. Flavonoid intake and risk of chronic diseases. Am J of Clin Nutr 2002; 76:560-568.
29. Ferrali M, Signorini C, Ciccoli L, Bambagioni S, Rossi V, Pompella A, et al. Protection of erythrocytes against oxidative damage and autologous immunoglobulin G (IgG) binding by iron chelator fluor-benzoil-pyridoxal hydrazone. Biochem Pharmacol 2000; 59:1365-1373.
30. Pavanato A, Tuñón MJ, Sánchez-Campos S, Marroni CA, Llesuy S, González-Gallego J, et al. Effects of quercetin on liver damage in rats with carbon tetrachloride-induced cirrhosis. Dig Dis Sci 2003; 48:824-829.
31. Khan S, Beigh S, Chaudhari BP, Sharma S, Aliul Hasan Abdi S, Ahmad S, et al. Mitochondrial dysfunction induced by Bisphenol A is a factor of its hepatotoxicity in rats. Environ Toxicol 2016; 31:1922-1934.
32. Zou W, Liu W, Yang B, Wu L, Yang J, Zou T, et al. quercetin protects against perfluorooctanoic acid-induced liver injury by attenuating oxidative stress and inflammatory response in mice. Int Immunopharmacol 2015; 28:129-135.
33. Reitman S, Frankel S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol 1957; 28:56-63.
34. Wenk MR, Fernandis AZ. A manual for biochemistry protocols: World Scientific; 2007.
35. Heidari M, Badri R, Rezaei M, Shushizadeh MR, Reza A. Mitochondrial protection against arsenic toxicity by a novel gamma tocopherol analogue in rat. Bull Env Pharmacol Life Sci 2015; 4:43-55.
36. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72:248-254.
37. Keshtzar E, Khodayar M, Javadipour M, Ghaffari M, Bolduc D, Rezaei M. Ellagic acid protects against arsenic toxicity in isolated rat mitochondria possibly through the maintaining of complex II. Hum Exp Toxicol 2016; 35:1060-1072.
38. Baracca A, Sgarbi G, Solaini G, Lenaz G. Rhodamine 123 as a probe of mitochondrial membrane potential: evaluation of proton flux through F0 during ATP synthesis. Biochim Biophysica Acta 2003; 1606:137-146.
39. Shirani M, Alizadeh S, Mahdavinia M, Dehghani MA. The ameliorative effect of quercetin on bisphenol A-induced toxicity in mitochondria isolated from rats. Environ Sci Pollut Res Int 2019; 1-9.
40. Zhang F, Xu Z, Gao J, Xu B, Deng Y. In vitro effect of manganese chloride exposure on energy metabolism and oxidative damage of mitochondria isolated from rat brain. Environ Toxicol Pharmacol 2008; 26:232-236.
41. Khodayar MJ, Kalantari H, Khorsandi L, Rashno M, Zeidooni L. Betaine protects mice against acetaminophen hepatotoxicity possibly via mitochondrial complex II and glutathione availability. Biomed Pharmacother 2018; 103:1436-1445.
42. Zhang T, Sun H, Kannan K. Blood and urinary bisphenol A concentrations in children, adults, and pregnant women from china: partitioning between blood and urine and maternal and fetal cord blood. Environ Sci Eechnol 2013; 47:4686-4694.
43. Moon MK, Kim MJ, Jung IK, Koo YD, Ann HY, Lee KJ, et al. Bisphenol A impairs mitochondrial function in the liver at doses below the no observed adverse effect level. J Korean Med Sci 2012; 27:644-652.
44. Rönn M, Kullberg J, Karlsson H, Berglund J, Malmberg F, Örberg J, et al. Bisphenol A exposure increases liver fat in juvenile fructose-fed Fischer 344 rats. Toxicology 2013; 303:125-132.
45. Doerge DR, Fisher JW, editors. Background paper on metabolism and toxicokinetics of bisphenol A. Proceedings of the WHO/HSE/FOS/111 Expert Meeting on Bisphenol A (BPA’10); 2010.
46. Suthar H, Verma R, Patel S, Jasrai Y. Green tea potentially ameliorates bisphenol A-induced oxidative stress: an in vitro and in silico study. Biochem Res Int 2014; 2014.
47. Xia W, Jiang Y, Li Y, Wan Y, Liu J, Ma Y, et al. Early-life exposure to bisphenol a induces liver injury in rats involvement of mitochondria-mediated apoptosis. PloS one 2014; 9:e90443.
48. Jiang Y, Xia W, Zhu Y, Li X, Wang D, Liu J, et al. Mitochondrial dysfunction in early life resulted from perinatal bisphenol A exposure contributes to hepatic steatosis in rat offspring. Toxicol Lett 2014; 228:85-92.
49. Magrane J, Cortez C, Gan W-B, Manfredi G. Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models. Hum Mol Genet 2013; 23:1413-1424.
50. Kabuto H, Hasuike S, Minagawa N, Shishibori T. Effects of bisphenol A on the metabolisms of active oxygen species in mouse tissues. Environ Res 2003; 93:31-35.
51. Ali N, Rashid S, Nafees S, Hasan SK, Shahid A, Majed F, et al. Protective effect of chlorogenic acid against methotrexate induced oxidative stress, inflammation and apoptosis in rat liver: An experimental approach. Chem Biol Interac 2017; 272:80-91.
52. Wan Y, Tang M, Chen X, Chen L, Wei Y, Wang Y. Inhibitory effect of liposomal quercetin on acute hepatitis and hepatic fibrosis induced by concanavalin A. Braz J Med Biol Res 2014; 47:655-661.
53. Ciftci O, Vardi N, Ozdemir I. Effects of quercetin and chrysin on 2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin induced hepatotoxicity in rats. Environ Toxicol 2013; 28:146-154.
54. Nabavi SF, Russo GL, Daglia M, Nabavi SM. Role of quercetin as an alternative for obesity treatment: you are what you eat! Food Chem 2015; 179:305-310.
55. Gardner CR, Mishin V, Laskin JD, Laskin DL. Exacerbation of acetaminophen hepatotoxicity by the anthelmentic drug fenbendazole. Toxicolo Sci 2011; 125:607-612.
56. Bresciani G, da Cruz IBM, González-Gallego J. Manganese superoxide dismutase and oxidative stress modulation.  Adv Clin Chem. 68: Elsevier; 2015. p. 87-130.
57. Olayinka ET, Ore A, Adeyemo OA, Ola OS, Olotu OO, Echebiri RC. Quercetin, a flavonoid antioxidant, ameliorated procarbazine-induced oxidative damage to murine tissues. Antioxidants 2015; 4:304-321.
58. Li X, Fang P, Mai J, Choi ET, Wang H, Yang X-f. Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol 2013; 6:19.
59. Miller KE, Sheetz MP. Axonal mitochondrial transport and potential are correlated. J cell Sci 2004; 117:2791-2804.
60. Carrasco-Pozo C, Mizgier ML, Speisky H, Gotteland M. Differential protective effects of quercetin, resveratrol, rutin and epigallocatechin gallate against mitochondrial dysfunction induced by indomethacin in Caco-2 cells. Chem Biol Interact 2012; 195:199-205.
61. Liu Y, Xie L, Zhao J, Huang X, Song L, Luo J, et al. Association between catalase gene polymorphisms and risk of chronic hepatitis B, hepatitis B virus-related liver cirrhosis and hepatocellular carcinoma in Guangxi population: a case–control study. Medicine 2015; 94.
62. Hassan ZK, Elobeid MA, Virk P, Omer SA, ElAmin M, Daghestani MH, et al. Bisphenol A induces hepatotoxicity through oxidative stress in rat model. Oxid Med Cell Longev 2012;2012:194829.