Skip to main content
Log in

Hesperidin ameliorates trichloroethylene-induced nephrotoxicity by abrogation of oxidative stress and apoptosis in wistar rats

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Trichloroethylene (TCE), a nephrotoxicant is known to cause severe damage to the kidney. In this study, the nephroprotective potential of hesperidin was evaluated against TCE-induced nephrotoxicity in wistar rats. Oral administration of TCE (1000 mg/kg b.wt) for 15 days enhanced renal lipid peroxidation and reduced antioxidant enzymes armoury viz., reduced renal glutathione, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, catalase and superoxide dismutase. It also enhanced the levels of blood urea nitrogen, creatinine and kidney injury molecule (KIM-1). Caspase-3 and bax expression were found to be elevated, while that of bcl-2 reduced suggesting that TCE induces apoptosis. However, pretreatment with hesperidin at a dose of 100 and 200 mg/kg b.wt for 15 days significantly decreased lipid peroxidation, increased the levels of antioxidant enzymes and reduced blood urea, creatinine and KIM-1 levels. Hesperidin also modulated the apoptotic pathways by altering the expressions of caspase-3, bax and bcl-2 to normal. Our results suggest that hesperidin can be used as a nephroprotective agent against TCE-induced nephrotoxicity.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

TCE:

1,1,2-Trichloroethylene

DCVG:

S-(1,2-dichlorovinyl)-l-glutathione

DCVC:

S-(1,2-dichlorovinyl)-l-cysteine

GPx:

Glutathione peroxidase

GSH:

Glutathione

GR:

Glutathione reductase

GST:

Glutathione-S-transferase

LPO:

Lipid peroxidation

MDA:

Malondialdehyde

PMS:

Post-mitochondrial supernatant

SOD:

Superoxide dismutase

BUN:

Blood urea nitrogen

KIM-1:

Kidney injury molecule

HS:

Hesperidin

ROS:

Reactive oxygen species

References

  1. Chiu WA, Jinot J, Scott CS, Makris SL, Cooper GS, Dzubow RC, Bale AS, Evans MV, Guyton KZ, Keshava N, Lipscomb JC, Barone S Jr, Fox JF, Gwinn MR, Schaum J, Caldwell JC (2013) Human health effects of trichloroethylene: key findings and scientific issues. Environ Health Perspect 121:303–311

    Article  PubMed Central  PubMed  Google Scholar 

  2. Lash LH, Qian W, Putt DA, Hueni SE, Elfarra AA, Krause RJ, Parker JC (2001) Renal and hepatic toxicity of trichloroethylene and its glutathione-derived metabolites in rats and mice: sex-, species-, and tissue-dependent differences. Pharmacol Exp Ther 297:155–164

    CAS  Google Scholar 

  3. NRC (National Research Council) (2006) Assessing the human health risks of trichloroethylene: key scientific issues. The National Academies Press, Washington, DC

    Google Scholar 

  4. Zhao Y, Krishnadasan A, Kennedy N, Morgenstern H, Ritz B (2005) Estimated effects of solvents and mineral oils on cancer incidence and mortality in a cohort of aerospace workers. Am J Ind Med 48:249–258

    Article  CAS  PubMed  Google Scholar 

  5. Charbotel B, Fevotte J, Hours M, Martin JL, Bergeret A (2006) Case-control study on renal cell cancer and occupational exposure to trichloroethylene. Part II: epidemiological aspects. Ann Occup Hyg 50:777–787

    Article  CAS  PubMed  Google Scholar 

  6. Moore L, Boffetta P, Karami S, Brennan P, Stewart P, Hung R, Zaridze D, Matveev V, Janout V, Kollarova H, Bencko V, Navratilova M, Szeszenia-Dabrowska N, Mates D, Gromiec J, Holcatova I, Merino M, Chanock S, Chow W, Rothman N (2010) Occupational trichloroethylene exposure and renal carcinoma risk: evidence of genetic susceptibility by reductive metabolism gene variants. Cancer Res 70:6527–6536

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Lock EJ, Reed CJ (2006) Trichloroethylene: mechanisms of renal toxicity and renal cancer and relevance to risk assessment. Toxicol Sci 91:313–331

    Article  CAS  PubMed  Google Scholar 

  8. Lock EA (2010) Renal xenobiotic metabolism. In: McQueen CA (ed) Comprehensive toxicolology. Elsevier, Liverpool, pp 55–79

    Chapter  Google Scholar 

  9. Lash LH, Fisher JW, Lipscomb JC, Parker JC (2000) Metabolism of trichloroethylene. Environ Health Perspect 108:177–200

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Liu RH (2004) Potential synergy of phytochemicals in cancer prevention: mechanism of action. J Nutr 134:3479–3485

    Google Scholar 

  11. Mates JM, Segura JA, Alonso FJ, Márquez J (2011) Anticancer antioxidant regulatory functions of phytochemicals. Curr Med Chem 18:2315–2338

    Article  CAS  PubMed  Google Scholar 

  12. Fu Z, Zhen W, Yuskavage J, Liu D (2011) Epigallocatechin gallate delays the onset of type 1 diabetes in spontaneous non-obese diabetic mice. Br J Nutr 105:1218–1225

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Hail N Jr, Cortes M, Drake E, Spallholz J (2008) Cancer chemoprevention: a radical perspective. Free Radic Biol Med 45:97–110

    Article  CAS  PubMed  Google Scholar 

  14. Tan AC, Konczak I, Sze DM, Ramzan I (2011) Molecular pathways for cancer chemoprevention by dietary phytochemicals. Nutr Cancer 63:495–505

    Article  CAS  PubMed  Google Scholar 

  15. Assini JM, Mulvihill EE, Huff MW (2013) Citrus flavonoids and lipid metabolism. Curr Opin Lipidol 24:34–40

    Article  CAS  PubMed  Google Scholar 

  16. Izzi V, Masuelli L, Tresoldi I, Sacchetti P, Modesti A, Galvano F, Bei R (2012) The effects of dietary flavonoids on the regulation of redox inflammatory networks. Front Biosci 17:2396–2418

    Article  Google Scholar 

  17. Kay CD, Hooper L, Kroon PA, Rimm EB, Cassidy A (2012) Relative impact of flavonoid composition, dose and structure on vascular function: a systematic review of randomized controlled trials of flavonoid-rich food products. Mol Nutr Food Res 56:1605–1616

    Article  CAS  PubMed  Google Scholar 

  18. Clere N, Faure S, Martinez MC, Andriantsitohaina R (2011) Anticancer properties of flavonoids: roles in various stages of carcinogenesis. Cardiovasc Hematol Agents Med Chem 9:62–77

    Article  CAS  PubMed  Google Scholar 

  19. Wilmsen PK, Spada DS, Salvador M (2005) Antioxidant activity of the flavonoid hesperidin in chemical and biological systems. J Agric Food Chem 53:4757–4761

    Article  CAS  PubMed  Google Scholar 

  20. Berkarda B, Koyuncu H, Soybir G, Baykut F (1998) Inhibitory effect of hesperidin on tumour initiation and promotion in mouse skin. Res Exp Med (Berl) 198:93–99

    Article  CAS  Google Scholar 

  21. Lee CJ, Wilson L, Jordan MA, Nguyen V, Tang J, Smiyun G (2010) Hesperidin suppressed proliferations of both human breast cancer and androgen-dependent prostate cancer cells. Phytother Res 24:S15–S19

    Article  PubMed  Google Scholar 

  22. Kamaraj S, Anandakumar P, Jagan S, Ramakrishnan G, Devaki T (2011) Hesperidin attenuates mitochondrial dysfunction during benzo(a)pyrene-induced lung carcinogenesis in mice. Fundam Clin Pharmacol 25:91–98

    Article  CAS  PubMed  Google Scholar 

  23. Saiprasad G, Chitra P, Manikandan R, Sudhandiran G (2013) Hesperidin alleviates oxidative stress and downregulates the expressions of proliferative and inflammatory markers in azoxymethane-induced experimental coloncarcinogenesis in mice. Inflamm Res 62:425–440

    Article  CAS  PubMed  Google Scholar 

  24. Kaur G, Tirkey N, Chopra K (2006) Beneficial effect of hesperidin on lipopolysaccharide-induced hepatotoxicity. Toxicology 226:152–160

    Article  CAS  PubMed  Google Scholar 

  25. Anandan R, Subramanian P (2012) Renal protective effect of hesperidin on gentamicin-induced acute nephrotoxicity in male Wistar albino rats. Redox Rep 17:219–226

    Article  CAS  PubMed  Google Scholar 

  26. Sahu BD, Kuncha M, Sindhura GJ, Sistla R (2013) Hesperidin attenuates cisplatin-induced acute renal injury by decreasing oxidative stress, inflammation and DNA damage. Phytomedicine 20:453–460

    Article  CAS  PubMed  Google Scholar 

  27. Khan S, Priyamvada S, Khan SA, Khan W, Farooq N, Khan F, Yusufi AN (2009) Effect of trichloroethylene (TCE) toxicity on the enzymes of carbohydrate metabolism, brush border membrane and oxidative stress in kidney and other rat tissues. Food Chem Toxicol 47:1562–1568

    Article  CAS  PubMed  Google Scholar 

  28. Ahmad ST, Sultana S (2011) Tannic acid mitigates cisplatin-induced nephrotoxicity in mice. Hum Exp Toxicol 31:145–156

    Article  PubMed  Google Scholar 

  29. Wright JR, Colby HD, Miles PR (1981) Cytosolic factors which affect microsomal lipid peroxidation in lung and liver. Arch Biochem Biophys 206:296–304

    Article  CAS  PubMed  Google Scholar 

  30. Jollow DJ, Mitchell JR, Zampaglione N, Gillete JR (1974) Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11:151–169

    Article  CAS  PubMed  Google Scholar 

  31. Mohandas J, Marshall JJ, Duggin GG, Horvath JS, Tiller DJ (1984) Differential distribution of glutathione and glutathione-related enzymes in rabbit kidney: possible implications in analgesic nephropathy. Biochem Pharmacol 33:1801–1807

    Article  CAS  PubMed  Google Scholar 

  32. Carlberg I, Mannervik B (1975) Glutathione reductase levels in rat brain. J Biol Chem 250:5475–5479

    CAS  PubMed  Google Scholar 

  33. Claiborne A (1985) Catalase activity. In: Greenwald RA (ed) CRC handbook of methods in oxygen radical research. CRC, Boca Raton, pp 283–284

    Google Scholar 

  34. Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47:469–474

    Article  CAS  PubMed  Google Scholar 

  35. Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferases. J Biol Chem 249:7130–7139

    CAS  PubMed  Google Scholar 

  36. Kanter M (1975) Clinical chemistry. The Bobber Merrill Company Inc, Indianapolis

    Google Scholar 

  37. Hare RS (1950) Endogenous creatinine in serum and urine. Proc Soc Exp Biol Med 74:148–151

    Article  CAS  PubMed  Google Scholar 

  38. Lowry OH, Rosebrough NJ, Farr AL, Randall RJL (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  39. Cojocel C, Beuter W, Müller W, Mayer D (1989) Lipid peroxidation: a possible mechanism of trichloroethylene-induced nephrotoxicity. Toxicology 55:131–141

    Article  CAS  PubMed  Google Scholar 

  40. McGoldrick TA, Lock EA, Rodilla V, Hawksworth GM (2003) Renal cysteine conjugate C-S lyase mediated toxicity of halogenated alkenes in primary cultures of human and rat proximal tubule cells. Arch Toxicol 77:365–370

    Article  CAS  PubMed  Google Scholar 

  41. Vaidya VS, Shankar L, Lock EA, Bucci TJ, Mehendale HM (2003) Renal injury and repair following S-1,2-dichlorovinyl-l-cysteine administration to mice. Toxicol Appl Pharmacol 188:110–121

    Article  CAS  PubMed  Google Scholar 

  42. Tripoli E, Guardia ML, Giammanco S, Majo DD, Giammanco M (2007) Citrus flavonoids: molecular structure, biological activity and nutritional properties: a review. Food Chem 104:466–479

    Article  CAS  Google Scholar 

  43. Williams RJ, Spencer JPE, Rice-Evans C (2004) Serial review: flavonoids and isoflavonones (Phytoestrogens): absorption, metabolism and bioactivity. Free Radic Biol Med 36:838–849

    Article  CAS  PubMed  Google Scholar 

  44. Cushnie TPT, Lamb AJ (2005) Antimicrobial activity of flavonoids. Int J Antimicrob Agents 26:343–356

    Article  CAS  PubMed  Google Scholar 

  45. Sharififar F, Dehghn-Nudeh G, Mirtajaldini M (2009) Major flavonoids with antioxidant activity from Teucrium polium. Food Chem 112:885–888

    Article  CAS  Google Scholar 

  46. Pal RS, Ariharasivakumar G, Girhepunjhe K, Upadhay A (2009) In-vitro antioxidative activity of phenolic and flavonoids compounds extracted from seeds of Abrus precatorius. Int J Pharm Sci 1:136–140

    CAS  Google Scholar 

  47. Garg A, Garg S, Zaneveld LJD, Singla AK (2001) Chemistry and pharmacology of the citrus bioflavonoid hesperidin. Phytother Res 15:655–669

    Article  CAS  PubMed  Google Scholar 

  48. Tanaka T, Tanaka T, Tanaka M, Kuno T (2012) Cancer chemoprevention by citrus pulp and juices containing high amounts of β-cryptoxanthin and hesperidin. J Biomed Biotechnol 2012:1–10

    Article  Google Scholar 

  49. Kohen R, Nyska A (2002) Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol 30:620–630

    Article  CAS  PubMed  Google Scholar 

  50. Marnett LJ (1999) Lipid peroxidation-DNA damage by malondialdehyde. Mutat Res 424:83–95

    Article  CAS  PubMed  Google Scholar 

  51. Kunwar A, Priyadarsini KI (2011) Free radicals, oxidative stress and importance of antioxidants in human health. J Med Allied Sci 1:53–60

    Google Scholar 

  52. Torasson M, Clark J, Dankovic D, Mathias P, Skaggs S, Walker C, Werren D (1999) Oxidativestress and DNA damage in Fisher rats following acute exposure to trichloroethylene or perchloroethylene. Toxicology 138:43–53

    Article  Google Scholar 

  53. Tabrez S, Ahmad M (2011) Some enzymatic/nonenzymatic antioxidants as potential stress biomarkers of trichloroethylene, heavy metal mixture, and ethyl alcohol in rat tissues. Environ Toxicol 26:207–216

    Article  CAS  PubMed  Google Scholar 

  54. Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF (2003) The changing faces of glutathione, a cellular protagonist. Biochem Pharmacol 66:1499–1503

    Article  CAS  PubMed  Google Scholar 

  55. Ahmadi A, Hosseinimehr SJ, Naghshvar F, Hajir E, Ghahremani M (2008) Chemoprotective effects of hesperidin against genotoxicity induced by cyclophosphamide in mice bone marrow cells. Arch Pharmacol Res 31:794–797

    Article  CAS  Google Scholar 

  56. Abdel-Raheem IT, Abdel-Ghany AA (2009) Hesperidin alleviates doxorubicin-induced cardiotoxicity in rats. J Egypt Natl Cancer Inst 21:175

    Google Scholar 

  57. Pires Das Neves RN, Carvalho F, Carvalho M, Fernandes E, Soares E, Bas-tos MDL, Pereira MDL (2004) Protective activity of hesperidin and lipoic acid against sodium arsenite acute toxicity in mice. Toxicol Pathol 32:527–535

    Article  CAS  Google Scholar 

  58. Ibrahim SS (2008) Protective effect of hesperidin, a citrus bioflavonoid, on 693 diabetes-induced brain damage in rats. J Appl Sci Res 4:84–95

    CAS  Google Scholar 

  59. Tirkey N, Pilkhwal S, Kuhad A, Chopra K (2005) Hesperidin, a citrus bioflavonoid, decreases the oxidative stress produced by carbon tetrachloride in rat liver and kidney. BMC Pharmacol 5:2

    Article  PubMed Central  PubMed  Google Scholar 

  60. Gharib OA, Gharib MA (2008) Kombucha tea ameliorates trichloroethylene induced hepatic damages in rats via inhibition of oxidative stress and free radicals induction. Egypt J Sci Appl 21:481–498

    Google Scholar 

  61. Bonventre JV (2009) Kidney injury molecule-1 (KIM-1): a urinary biomarker and much more. Nephrol Dial Transpl 24:3265–3268

    Article  CAS  Google Scholar 

  62. Bonventre JV, Yang L (2010) Kidney injury molecule-1. Curr Opin Crit Care 16:556–561

    Article  PubMed  Google Scholar 

  63. Pop C, Salvesen GS (2009) Human caspases: activation, specificity, and regulation. J Biol Chem 284:21777–21781

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Porter AG (2006) Flipping the safety catch of procaspase-3. Nat Chem Biol 2:509–510

    Article  CAS  PubMed  Google Scholar 

  65. Xu F, Papanayotou I, Putt DA, Wang J, Lash LH (2008) Role of mitochondrial dysfunction in cellular responses to S-(1,2-dichlorovinyl)-l-cysteine in primary cultures of human proximal tubular cells. Biochem Pharmacol 76:552–567

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Hacker G, Weber A (2007) BH3-only proteins trigger cytochrome c release, but how? Arch Biochem Biophys 462:150–155

    Article  PubMed  Google Scholar 

  67. Carthy CM, Yanagawa B, Luo H, Granville DJ, Yang D, Cheung P, Cheung C, Esfandiarei M, Rudin CM, Thompson CB, Hunt DWC, McManus BM (2003) Bcl-2 and Bcl-xL overexpression inhibits cytochrome c release, activation of multiple caspases, and virus release following coxsackievirus B3 infection. Virology 313:147–157

    Article  CAS  PubMed  Google Scholar 

  68. Lalier L, Cartron PF, Juin P, Nedelkina S, Manon S, Bechinger B, Vallette FM (2007) Bax activation and mitochondrial insertion during apoptosis. Apoptosis 12:887–896

    Article  CAS  PubMed  Google Scholar 

  69. Teijido O, Dejean L (2010) Upregulation of Bcl2 inhibits apoptosis-driven BAX insertion but favors BAX relocalization in mitochondria. FEBS Lett 584:3305–3310

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The author (SS), Jamia Hamdard University acknowledge the help given to the student (AS) for getting registered to PhD in Indira Gandhi National Open University, New Delhi, India.

Conflict of interest

The authors of the present research work do not have any conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sarwat Sultana.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Siddiqi, A., Nafees, S., Rashid, S. et al. Hesperidin ameliorates trichloroethylene-induced nephrotoxicity by abrogation of oxidative stress and apoptosis in wistar rats. Mol Cell Biochem 406, 9–20 (2015). https://doi.org/10.1007/s11010-015-2400-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-015-2400-8

Keywords

Navigation