Skip to main content
Log in

ORY supplementation mitigates acetaminophen-induced acute liver failure in male mice: role of oxidative stress and apoptotic markers

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

The aim of the present study was to assess the possible protective effect of γ-oryzanol (ORY) supplementation in a model of acute liver failure (ALF) induced by acetaminophen (APAP) in mice. Male Swiss strain mice were supplemented with ORY (10 and 50 mg/kg, per oral route) daily for 7 days. One hour after the last supplementation, animals received APAP (300 mg/kg, intraperitoneal). Twenty-four hours after APAP administration, mice were euthanized, and biochemical and histopathological determinations were performed. Histopathological analysis revealed that APAP caused vascular congestion, loss of cellular structure, and cellular infiltration in hepatocytes. Moreover, it caused oxidative damage (enzymatic and non-enzymatic analysis of oxidative stress), with loss of hepatic function leading to cell apoptosis (apoptotic parameters). ORY supplementation (ORY-10 and ORY-50) protected against all changes in ALF model. Thus, the protective effect of ORY supplementation was due to modulation of antioxidant defenses avoiding the apoptotic process.

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

Similar content being viewed by others

References

  • Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126

    CAS  PubMed  Google Scholar 

  • Bancroft JD, Stevens A, Turner DR (1996) Theory and practice of histological techniques, 4th edn. Churchill Livingstone, New York

    Google Scholar 

  • Bhaskaragoud G, Rajath S, Mahendra VP, Kumar G, Krishna AG, Kumar GS (2016) Hypolipidemic mechanism of oryzanol components-ferulic acid and phytosterols. Biochem Biophys Res Commun 476:82–89

    CAS  PubMed  Google Scholar 

  • Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    CAS  Google Scholar 

  • Carlberg I, Mannervik B (1985) Glutathione reductase. Methods Enzymol 113:484–490

    CAS  PubMed  Google Scholar 

  • Chen Q, Yan D, Zhang O, Zhang G, Xia M, Li J, Zhan W, Shen E, Li Z, Lin L, Chen HY, Wan X (2020) Treatment of acetaminophen-induced liver failure by blocking the death checkpoint protein TRAIL. Biochim Biophys Acta 1866:16558

    Google Scholar 

  • Chotimarkorn C, Ushio H (2008) The effect of trans-ferulic acid and gamma-oryzanol on ethanol-induced liver injury in C57BL mouse. Phytomedicine 15:951–958

    CAS  PubMed  Google Scholar 

  • De Gomes MG, Donato F, Souza LC, Goes AR, Filho CB, Del Fabbro L, Bianchini MC, Hassan W, Boeira SP, Puntel RL, Jesse CR (2018) γ-Oryzanol supplementation modifies the inflammatory and oxidative response in fulminant hepatic failure in mice. PharmaNutrition 6:191–197

    Google Scholar 

  • De Gomes MG, Del Fabbro L, Goes AR, Souza LC, Boeira SP, Haas SE, Puntel RL, Jesse CR (2019) Supplementation with gamma oryzanol ameliorates CCl4-induced hepatic fibrosis in mice. PharmaNutrition 10:100169

    Google Scholar 

  • El-Hassan H, Anwar K, Macanas-Pirard P, Crabtree M, Chow SC, Johnson VL, Lee PC, Hinton RH, Price SC, Kass GE (2003) Involvement of mitochondria in acetaminophen-induced apoptosis and hepatic injury: roles of cytochrome c, Bax, Bid, and caspases. Toxicol Appl Pharmacol 191:118–129

    CAS  PubMed  Google Scholar 

  • Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    CAS  PubMed  Google Scholar 

  • Gupta A, Rawat AK (2017) Antioxidant and hepatoprotective potential of phenol-rich fraction of Juniperus communis Linn. leaves. Pharmacogn Mag 13:108–113

    PubMed  PubMed Central  Google Scholar 

  • Habig W, Pabst M, Jokoby W (1974) Glutathione S-transferases, the first enzymatic step in mercapturic acid formation. J Biol Chem 249:7130–7139

    CAS  PubMed  Google Scholar 

  • Helal MG, Samra YA (2020) Irbesartan mitigates acute liver injury, oxidative stress, and apoptosis induced by acetaminophen in mice. J Biochem Mol Toxicol 22:22447

    Google Scholar 

  • Jacques-Silva MC, Nogueira CW, Broch L, Rocha JBT (2001) Diphenyl diselenide and ascorbic acid changes deposition of selenium and ascorbic acid in brain of mice. Pharmacol Toxicol 88:119–125

    CAS  PubMed  Google Scholar 

  • Jaeschke H, Duan L, Akakpo JY, Farhood A, Ramachandran A (2018) The role of apoptosis in acetaminophen hepatotoxicity. Food Chem Toxicol 118:709–718

    CAS  PubMed  PubMed Central  Google Scholar 

  • Larsen FS, Wendon J (2014) Understanding paracetamol-induced liver failure. Intensive Care Med 40:888–890

    PubMed  Google Scholar 

  • Mandal M, Gardner CR, Sun R, Choi H, Lad S, Mishin V, Laskin JD, Laskin DL (2016) The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury. Toxicol Appl Pharmacol 304:110–120

    CAS  PubMed  PubMed Central  Google Scholar 

  • McGill MR, Jaeschke H (2014) Mechanistic biomarkers in acetaminophen-induced hepatotoxicity and acute liver failure: from preclinical models to patients. Expert Opin Drug Metab Toxicol 10:1005–1017

    CAS  PubMed  PubMed Central  Google Scholar 

  • Meister A (1984) Glutathione ascorbic acid antioxidant system in animals. J Biol Chem 269:9397–9400

    Google Scholar 

  • Minatel IO, Francisqueti FV, Correa CR, Lima GP (2016) Antioxidant activity of gamma-oryzanol: a complex network of interactions. Int J Mol Sci 17:1107

    PubMed Central  Google Scholar 

  • Misra H, Fridovich I (1972) The role of superoxide anion in the autoxidation of epinephrine and simple assay for superoxide dismutase. J Biol Chem 247:3170–3175

    CAS  PubMed  Google Scholar 

  • Moon S, Kim D, Shimizu N, Okada T, Hitoe S, Shimoda H (2016) Ninety-day oral toxicity study of rice-derived γ-oryzanol in Sprague-dawley rats. Toxicol Rep 4:9–18

    PubMed  PubMed Central  Google Scholar 

  • Ohara K, Kiyotani Y, Uchida A, Nagasaka R, Maehara H, Kanemoto S, Hori M, Ushio H (2001) Oral administration of γ-aminobutyric acid and γ-oryzanol prevents stress-induced hypoadiponectinemia. Phytomedicine 18:655–660

    Google Scholar 

  • Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    CAS  PubMed  Google Scholar 

  • Opdenbosch NV, Lamkanfi M (2019) Caspases in cell death, inflammation, and disease. Immunity 50:1352–1364

    PubMed  PubMed Central  Google Scholar 

  • Panchal SS, Patidar RK, Jha AB, Allam AA, Ajarem J, Butani SB (2017) Anti-inflammatory and antioxidative stress effects of oryzanol in glaucomatous rabbits. J Ophthalmol 1468716

  • Sakamoto K, Tabata T, Shirasaki K, Inagaki T, Nakayama S (1987) Effects of γ-oryzanol and cycloartenol ferulic acid ester on cholesterol diet induced hyperlipidemia in rats. Jpn J Pharmacol 45:559–565

    CAS  PubMed  Google Scholar 

  • Sassa S (1982) Delta-aminolevulinic acid dehydratase assay. Enzyme 28:133–145

    CAS  PubMed  Google Scholar 

  • Seo M, Kim H, Lee JH, Park J (2020) Pelargonidin ameliorates acetaminophen-induced hepatotoxicity in mice by inhibiting the ROS-induced inflammatory apoptotic response. Biochimie 168:10–16

    CAS  PubMed  Google Scholar 

  • Shu G, Qiu Y, Hao J, Fu Q, Deng X (2019) γ-Oryzanol alleviates acetaminophen induced liver injury: roles of modulating AMPK/GSK3β/Nrf2 and NF-κB signaling pathways. Food Funct 10:6858

    CAS  PubMed  Google Scholar 

  • Southorn PA, Powis G (1988) Free radicals in medicine I. Nature and biologic reactions. Mayo Clin Proc 63:381–389

    CAS  PubMed  Google Scholar 

  • Suliman HB, Piantadosi CA (2016) Mitochondrial quality control as a therapeutic target. Pharmacol Rev 68:20–48

    CAS  PubMed  Google Scholar 

  • Wendel A (1981) Glutathione peroxidase. Methods Enzymol 177:325–333

    Google Scholar 

  • Woolbright BL, Jaeschke H (2017) Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure. J Hepatol 66:836–848

    CAS  PubMed  Google Scholar 

  • Yu Y, Zhang J, Wan J, Sun B (2019) The anti-cancer activity and potential clinical application of rice bran extracts and fermentation products. RSC Adv 9:18060–18069

    CAS  Google Scholar 

  • Zhang HY, Wang HL, Zhong GH, Zhu JX (2018) Molecular mechanism and research progress on pharmacology of traditional Chinese medicine in liver injury. Pharm Biol 56:594–611

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng R, Dragomir AC, Mishin V, Richardson JR, Heck DE, Laskin DL, Laskin JD (2014) Differential metabolism of 4-hydroxynonenal in liver, lung and brain of mice and rats. Toxicol Appl Pharmacol 279:43–52

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zolali E, Asgharian P, Hamishehkar H, Kouhsoltani M, Khodaii H, Hamishehkar H (2015) Effects of gamma oryzanol on factors of oxidative stress and sepsis-induced lung injury in experimental animal model. Iran J Basic Med Sci 18:1257–1263

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

Special thanks to C.R.J for making the study possible.

Funding

This study was financially supported by the Federal University of Pampa. This study was financed in part by the Coordination for the Improvement of Higher Education Personnel - Brazil (CAPES) – Finance Code 001.

Author information

Authors and Affiliations

Authors

Contributions

M.G.G: Conceptualization and writing. L.D.F., A.R.G., L.C.S., S.P.B, and C.R.J.: experimental methodology. All listed authors have agreed to the final submission of manuscript. In addition, the authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Marcelo Gomes de Gomes.

Ethics declarations

Mice were used according to the National Institutes of Health guide for the care and use of Laboratory animals (NIH Publications No. 8023, revised 1978) and guidelines of the Committee on Care and Use of Experimental Animal Resources of the Federal University of UNIPAMPA, Uruguaiana, Brazil. (Protocol 021/2014).

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(XLSX 54 kb).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Gomes, M.G., Del Fabbro, L., Goes, A.R. et al. ORY supplementation mitigates acetaminophen-induced acute liver failure in male mice: role of oxidative stress and apoptotic markers. Naunyn-Schmiedeberg's Arch Pharmacol 393, 2129–2137 (2020). https://doi.org/10.1007/s00210-020-01930-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-020-01930-1

Keywords

Navigation