Veterinary Research Forum

Hepatoprotective effect of royal jelly on dibutyl phthalate-induced liver injury in rats

Document Type : Original Article

Authors

Mahdieh Nezami Majd 1
Goudarz Sadeghi-Hashjin 1
Hassan Malekinejad 2
Ali Rassouli 1

1 Department of Comparative Biosciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran

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

https://doi.org/10.30466/vrf.2024.2033878.4338
Abstract
Phthalate esters, such as dibutyl phthalate (DBP), are extensively utilized and human and animal exposure leads to serious toxic effects, including hepatotoxicity. In the present study the protective effects of royal jelly (RJ) on DBP-induced liver damage was investigated. A total number of 40 Wistar albino rats were randomly divided into eight groups (n = 5): control (corn oil), DBP (500 mg kg-1), RJ (200 mg kg1), Quercetin (QCN; 50.00 mg kg-1), RJ (100 mg kg-1) + DBP, RJ (200 mg kg-1) + DBP, RJ (300 mg kg-1) + DBP, QCN (50.00 mg kg-1) + DBP. After 28 days of daily oral gavage treatment, animals were euthanized. The insulin resistance index, lipid profile and hepatic enzymes were measured on the collected serum samples. Moreover, oxidative and nitrosative stress biomarkers were determined in the liver. Histopathological alterations and ultimately cytochrome P450 2E1 (CYP2E1) activity was also assessed. Data obtained revealed that RJ significantly reduced the insulin resistance index and liver enzymes level in RJ-DBP groups. At the same time, RJ recovered the DBP-induced oxidative stress and restored the DBP-depleted glutathione. Moreover, RJ improved lipid profile and reduced significantly the DBP-induced hepatic CYP 2E1 activity in RJ-DBP groups. Dibutyl phthalate induced-hepatic damage such as necrosis of hepatocytes and scattered bleeding was alleviated in RJ-DBP group. Our data suggested that the administration of RJ could protect the DBP-induced hepatic functional and structural alterations. The RJ protective effects might be attributed to its antioxidant and anti-inflammatory properties and reduced CYP 2E1 activity.

Keywords

Dibutyl phthalate
Hepatotoxicity
Inflammation
Insulin resistance
Oxidative stress
Subjects
  1. Hannon PR, Flaws JA. The effects of phthalates on the ovary. Front Endocrinol (Lausanne) 2015; 6: 8. doi: 10. 3389/fendo.2015.00008.
  2. Radha MJ, Basha PM. Hepatotoxic evaluation of Di-n-butyl phthalate in Wistar rats upon sub-chronic exposure: a multigenerational assessment. Toxicol Rep 2020; 7: 772-778.
  3. Chen X, Xu S, Tan T, et al. Toxicity and estrogenic endocrine disrupting activity of phthalates and their mixtures. Int J Environ Res Public Health 2014; 11(3): 3156-3168.
  4. Gao H, Cheng Q-Y, Zhang C, et al. Association between phthalate exposure and insulin resistance: a review. Appl Ecol Environ Res 2022; 20(2): 1189-1197.
  5. James-Todd T, Stahlhut R, Meeker JD, et al. Urinary phthalate metabolite concentrations and diabetes among women in the National Health and Nutrition Examination Survey (NHANES) 2001-2008. Environ Health Perspect 2012; 120(9): 1307-1313.
  6. Sun Q, Cornelis MC, Townsend MK, et al. Association of urinary concentrations of bisphenol A and phthalate metabolites with risk of type 2 diabetes: a prospective investigation in the Nurses’ Health Study (NHS) and NHSII cohorts. Environ Health Perspect 2014; 122(6): 616-623.
  7. Stahlhut RW, van Wijngaarden E, Dye TD, et al. Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult US males. Environ Health Perspect 2007; 115(6): 876-882.
  8. Ore A, Adewale AA, Kehinde SA, et al. Potential roles of oxidative stress and insulin resistance in diisononyl phthalate induced dyslipidemia and hepatosteatosis in BALB/c mice. Adv Redox Res 2022; 5: 100038. doi: 10.1016/j.arres.2022.100038.
  9. Khan RS, Bril F, Cusi K, et al. Modulation of insulin resistance in nonalcoholic fatty liver disease. Hepatology 2019; 70(2): 711-724.
  10. Zhang W, Shen X, Zhang WW, et al. Di-(2-ethylhexyl) phthalate could disrupt the insulin signaling pathway in liver of SD rats and L02 cells via PPARγ. Toxicol Appl Pharmacol 2017; 316: 17-26.
  11. Yang R, Zheng J, Qin J, et al. Dibutyl phthalate affects insulin synthesis and secretion by regulating the mitochondrial apoptotic pathway and oxidative stress in rat insulinoma cells. Ecotoxicol Environ Saf 2023; 249: 114396. doi: 10.1016/j.ecoenv.2022.114396.
  12. Bugianesi E, Moscatiello S, Ciaravella MF, et al. Insulin resistance in nonalcoholic fatty liver disease. Curr Pharm Des 2010; 16(17): 1941-1951.
  13. Ahmad S, Campos MG, Fratini F, et al. New insights into the biological and pharmaceutical properties of royal jelly. Int J Mol Sci 2020; 21(2): 382. doi: 10.3390/ijms21020382.
  14. Zamami Y, Takatori S, Goda M, et al. Royal jelly ameliorates insulin resistance in fructose-drinking rats. Biol Pharm Bull 2008; 31(11): 2103-2107.
  15. Yoshida M, Hayashi K, Watadani R, et al. Royal jelly improves hyperglycemia in obese/diabetic KK-Ay mice. J Vet Med Sci 2017; 79(2): 299-307.
  16. Metwally Ibrahim SEL, Kosba AA. Royal jelly supplementation reduces skeletal muscle lipotoxicity and insulin resistance in aged obese rats. Pathophysiology 2018; 25(4): 307-315.
  17. Abdelsalam HM, Diab AA, Hussien AG, et al. Ginseng and royal jelly diminish diabetic hepato-and nephron-toxicity in STZ-induced diabetic male rats. Nutrire 2023; 48: 8. doi: 10.1186/s41110-023-00191-1.
  18. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28(7): 412-419.
  19. Benzie IF, Strain JJ. Ferric reducing/antioxidant power assay: direct measure of total antioxidant activity of biological fluids and modified version for simultaneous measurement of total antioxidant power and ascorbic acid concentration. Methods Enzymol 1999; 299: 15-27.
  20. Niehaus WG Jr, Samuelsson B. Formation of malonaldehyde from phospholipid arachidonate during microsomal lipid peroxidation. Eur J Biochem 1968; 6(1): 126-130.
  21. Green LC, Wagner DA, Glogowski J, et al. Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem 1982; 126(1): 131-138.
  22. Hu ML. Measurement of protein thiol groups and glutathione in plasma. Methods Enzymol 1994; 233: 380-385.
  23. Koop DR. Hydroxylation of p-nitrophenol by rabbit ethanol-inducible cytochrome P-450 isozyme 3a. Mol Pharmacol 1986; 29(4): 399-404.
  24. Lowry OH, Rosebrough NJ, Farr AL, et al. Protein measurement with the Folin phenol reagent. J biol Chem 1951; 193(1): 265-275.
  25. Zhang W, Li JY, Wei XC, et al. Effects of dibutyl phthalate on lipid metabolism in liver and hepatocytes based on PPARα/SREBP-1c/FAS/GPAT/AMPK signal pathway. Food Chem Toxicol 2021; 149: 112029. doi: 10.1016/j.fct.2021.112029.
  26. Shen C, Wei J, Wang T, et al. Acute toxicity and responses of antioxidant systems to dibutyl phthalate in neonate and adult Daphnia magna. PeerJ 2019; 7: e6584. doi: 10.7717/peerj.6584.
  27. Delkhoshe-Kasmaie F, Malekinejad H, Khoramjouy M, et al. Royal jelly protects from taxol-induced testicular damages via improvement of antioxidant status and up-regulation of E2f1. Syst Biol Reprod Med 2014; 60(2): 80-88.
  28. Tohamy HG, El-Neweshy MS, Soliman MM, et al. Protective potential of royal jelly against hydroxyurea-induced hepatic injury in rats via antioxidant, anti-inflammatory, and anti-apoptosis properties. PLoS One 2022; 17(3): e0265261. doi: 10.1371/journal. pone.0265261.
  29. Mondal S, Mukherjee S. Long-term dietary administration of diethyl phthalate triggers loss of insulin sensitivity in two key insulin target tissues of mice. Hum Exp Toxicol 2020; 39(7): 984-993.
  30. Evans JL, Maddux BA, Goldfine ID. The molecular basis for oxidative stress-induced insulin resistance. Antioxid Redox Signal 2005; 7(7-8): 1040-1052.
  31. You MM, Liu YC, Chen YF, et al. Royal jelly attenuates nonalcoholic fatty liver disease by inhibiting oxidative stress and regulating the expression of circadian genes in ovariectomized rats. J Food Biochem 2020; 44(3): e13138. doi: 10.1111/jfbc.13138.
  32. Moutsatsou P, Papoutsi Z, Kassi E, et al. Fatty acids derived from royal jelly are modulators of estrogen receptor functions. PLoS One 2010; 5(12): e15594. doi: 10.1371/journal.pone.0015594.
  33. Mishima S, Suzuki KM, Isohama Y, et al. Royal jelly has estrogenic effects in vitro and in vivo. J Ethnopharmacol 2005; 101(1-3): 215-220.
  34. Nuttall ME, Bradbeer JN, Stroup GB, et al. Idoxifene: a novel selective estrogen receptor modulator prevents bone loss and lowers cholesterol levels in ovariectomized rats and decreases uterine weight in intact rats. Endocrinology 1998; 139(12): 5224-5234.
  35. Ke HZ, Chen HK, Simmons HA, et al. Comparative effects of droloxifene, tamoxifen, and estrogen on bone, serum cholesterol, and uterine histology in the ovariectomized rat model. Bone 1997; 20(1): 31-39.
  36. Kashima Y, Kanematsu S, Asai S, et al. Identification of a novel hypocholesterolemic protein, major royal jelly protein 1, derived from royal jelly. PLoS One 2014; 9(8): e105073. doi: 10.1371/journal.pone.0105073.
  37. Wang S, Cao Y, Wang S, et al. DEHP induces immunosuppression through disturbing inflammatory factors and CYPs system homeostasis in common carp neutrophils. Fish Shellfish Immunol 2020; 96: 26-31.
  38. Shi YS, Zhao Y, Li XN, et al. Xenobiotic-sensing nuclear receptors as targets for phthalates-induced lung injury and antagonism of lycopene. Chemosphere 2023; 312(Pt 1): 137265. doi: 10.1016/j.chemosphere. 2022.137265.
  39. Leung TM, Nieto N. CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease. J Hepatol 2013; 58(2): 395-398.
  40. Kawabata K, Mukai R, Ishisaka A. Quercetin and related polyphenols: new insights and implications for their bioactivity and bioavailability. Food Funct 2015; 6(5): 1399-1417.
  41. Zhao X, Wang J, Deng Y, et al. Quercetin as a protective agent for liver diseases: a comprehensive descriptive review of the molecular mechanism. Phytother Res 2021; 35(9): 4727-4747.
  42. Xia LZ, Jiang MZ, Liu LL, et al. Protective effect of quercetin against phthalates induced hepatotoxicity in rats. Toxicol Res (Camb) 2022; 11(5): 863-871.
Veterinary Research Forum
Volume 16, Issue 2
February 2025
Pages 97-105

  • Receive Date 28 June 2024
  • Revise Date 03 August 2024
  • Accept Date 14 August 2024

Home

Guide for Authors

Submit Manuscript

Reviewers

Contact Us