EVALUATION AND STUDY OF PATHO-PHYSIOLOGICAL ROLE OF GLUCOCORTICOID RECEPTOR (GR) LIGANDS IN ACETAMINOPHEN-INDUCED LIVER INJURY IN MICE

M BATOOL; B ASLAM; F BATOOL

doi:10.54112/bcsrj.v2023i1.433

Authors

M BATOOL Institute of Pharmacy, Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan
B ASLAM Institute of Pharmacy, Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan
F BATOOL Department of Physiology, Government College University, Faisalabad, Pakistan

DOI:

https://doi.org/10.54112/bcsrj.v2023i1.433

Keywords:

Mice, Glucorticoid, Acetaminophen, AST, TAC, APAP

Abstract

Stress elicited by various drugs and psychosocial components is extensively prevalent globally. Glucocorticoid receptors control different features of lipid metabolism and lipoproteins in the liver. Acetaminophen or paracetamol is a broadly used antipyretic and analgesic drug. Overdose of acetaminophen causes centrilobular necrosis and fibrosis by generating oxidative stress. This experimental study was conducted to evaluate alone as well as combined systemic effects of glucocorticoid receptor (GR) ligands, Mifepristone (GR antagonist), and Dexamethasone (GR agonist) on oxidative damage and liver injury induced by acetaminophen. Evaluation of parameters of liver functions showed a substantial increase in AST ALT levels accompanied by elevation in TOS and reduction in TAC in the APAP-induced hepatotoxic group. While the groups that received dexamethasone, RU-486, and Dex+RU-486 as pretreatment significantly decreased the ALT, AST, and TOS levels compared to the toxic group (APAP). The protective effects of glucocorticoid receptor ligands in APAP-induced liver injury were further verified by histopathological examination. However, additional studies are necessary to illustrate the hepato-protective efficacy, safety profile, basic underlying process of protection, and therapeutic applications of glucocorticoid receptor ligands.

Downloads

Download data is not yet available.

References

Aithal GP, Watkins PB, Andrade RJ, et al., 2011. Case definition and phenotype standardization in drug‐induced liver injury. Clin. Pharmacol. Ther 89(6):806-815.

Andrade RJ, Robles M, Ulzurrun E and Lucena MI, 2009. Drug-induced liver injury: insights from genetic studies. Pharmacogenomics 10(9):1467-1487.

Banerjee S, Melnyk SB, Krager KJ, et al., 2017. Trifluoperazine inhibits acetaminophen-induced hepatotoxicity and hepatic reactive nitrogen formation in mice and in freshly isolated hepatocytes. Toxicol Rep 4:134-142.

Bjornsson ES, 2015. Drug-induced liver injury: an overview over the most critical compounds. Arch. Toxicol 89(3):327-334.

Blough E and Wu M, 2011. Acetaminophen: Beyond Pain and Fever-Relieving. Front Pharmacol 2:72.

Boonruamkaew P, Chonpathompikunlert P and Nagasaki Y, 2016. Redox Nanoparticle Therapeutics for Acetaminophen-Induced Hepatotoxicity in Mice. Oxid. med. cell. Longev 2016.

Botta D, Shi S, White CC, et al., 2006. Acetaminophen-induced liver injury is attenuated in male glutamate-cysteine ligase transgenic mice. J Biol Chem 281(39):28865-28875.

Burraco P and Gomez-Mestre I, 2016. Physiological stress responses in amphibian larvae to multiple stressors reveal marked anthropogenic effects even below lethal levels. Physiol Biochem Zool 89(6):462-472.

Cederbaum AI, 2015. Molecular mechanisms of the microsomal mixed function oxidases and biological and pathological implications. Redox Biol 4:60-73.

Chalasani N, Younossi Z, Lavine JE, et al., 2012. The diagnosis and management of non‐alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55(6):2005-2023.

Chawla A, Repa JJ, Evans RM and Mangelsdorf DJ, 2001. Nuclear receptors and lipid physiology: opening the X-files. Science 294(5548):1866-1870.

Chen M, Suzuki A, Borlak J, et al., 2015. Drug-induced liver injury: Interactions between drug properties and host factors. J. Hepatol 63(2):503-514.

Cichoz-Lach H and Michalak A, 2014. Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol 20(25):8082.

Cohen S, Gianaros PJ and Manuck SB, 2016. A stage model of stress and disease. Perspect Psychol Sci 11(4):456-463.

Cole MA, Kim PJ, Kalman BA and Spencer RL, 2000. Dexamethasone suppression of corticosteroid secretion: evaluation of the site of action by receptor measures and functional studies. Psychoneuroendocrinology 25(2):151-167.

de Sousa Rodrigues ME, Bekhbat M, Houser MC, et al., 2017. Chronic psychological stress and high-fat high-fructose diet disrupt metabolic and inflammatory gene networks in the brain, liver, and gut and promote behavioral deficits in mice. Brain Behav. Immun 59:158-172.

Deavall DG, Martin EA, Horner JM and Roberts R, 2012. Drug-induced oxidative stress and toxicity. J. Toxicol 2012.

Dendoncker K and Libert C, 2017. Glucocorticoid resistance as a major drive in sepsis pathology. Cytokine Growth Factor Rev.

Du K, Ramachandran A and Jaeschke H, 2016. Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential. Redox Biol 10:148-156.

Du SY, Zhang YL, Bai RX, et al., 2015. Lutein prevents alcohol-induced liver disease in rats by modulating oxidative stress and inflammation. Int J Clin Exp Med 8(6):8785.

Eken H, Ozturk H and Buyukbayram H, 2006. Dose-related effects of dexamethasone on liver damage due to bile duct ligation in rats. World J Gastroenterol 12(33):5379-5383.

Erel O, 2004. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin. Biochem 37:277-285.

Eriksen PL, Kreutzfeldt M, Grønbæk H, et al., 2017. Enrichment of Genetic Variants in the Glucocorticoid Receptor Signalling Pathway in Autoimmune Hepatitis with Failure of Standard Treatment. Basic Clin. Pharmacol. Toxicol.

Gammopathies MVP, 2005. Understanding and interpreting serum protein electrophoresis. Am Fam Physician 71:105-112.

Ghoumari AM, Dusart I, El-Etr M, et al., 2003. Mifepristone (RU486) protects Purkinje cells from cell death in organotypic slice cultures of postnatal rat and mouse cerebellum. Proc Natl Acad Sci 100(13):7953-7958.

Hamilton LA, Collins-Yoder A and Collins RE, 2016. Drug-Induced Liver Injury. AACN Adv Crit Care 27(4):430-440.

Heikinheimo O, Kekkonen R and Lahteenmaki P, 2003. The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action. Contraception 68(6):421–426.

Heitzer MD, Wolf IM, Sanchez ER, et al., 2007. Glucocorticoid receptor physiology. Rev Endocr Metab Disord 8(4):321–330.

Huang XJ, Choi YK, Im HS, et al., 2006. Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) detection techniques. Sensors 6(7):756-782.

Ivanov AV, Bartosch B, Smirnova OA, et al., 2013. HCV and oxidative stress in the liver. Viruses 5(2):439-469.

Ji L, Jiang P, Lu B, et al., 2013. Chlorogenic acid, a dietary polyphenol, protects acetaminophen-induced liver injury and its mechanism. J Nutr Biochem 24(11):1911-1919.

Kanel G and Korula J, 2005. Atlas of Liver Pathology (2nd Ed.). Atlas Surgic Pathol Saunders.

Khaderi SA and Hollinger FB, 2017. Is the Risk of Death Enhanced in Immunosuppressed Hepatitis B Virus–infected Patients Who Develop Acute Liver Failure?. Clin. Gastroenterol. Hepatol 15(1):123-126.

Konturek PC, Brzozowski T and Konturek SJ, 2011. Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options. J Physiol Pharmacol 62(6):591-599.

Leise MD, Poterucha JJ and Talwalkar JA, 2014. Drug-induced liver injury. Mayo Clin. Proc 89(1): 95-106.

Levenstein S, Rosenstock S, Jacobsen RK and Jorgensen T, 2015. Psychological stress increases risk for peptic ulcer, regardless of Helicobacter pylori infection or use of nonsteroidal anti-inflammatory drugs. Clin. Gastroenterol. Hepatol 13(3):498-506.

Levi L ed, 2016. Stress and distress in response to psychosocial stimuli: laboratory and real-life studies on sympatho-adrenomedullary and related reactions. Elsevier.

Li S, Hong M, Tan HY, et al., 2016. Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases. Oxid Med Cell Longev 2016.

Li S, Tan HY, Wang N, et al., 2015. The role of oxidative stress and antioxidants in liver diseases. Int. J. Mol. Sci 16(11):26087-26124.

Lucassen PJ, Oomen CA, Naninck EF, et al., 2015. Regulation of adult neurogenesis and plasticity by (early) stress, glucocorticoids, and inflammation. Cold Spring Harb Perspect Biol 7(9):021303.

Matsura T, Nishida T, Togawa A, et al., 2006. Mechanisms of protection by melatonin against acetaminophen‐induced liver injury in mice. J Pineal Res 41(3):211-219.

McGill MR, Williams CD, Xie Y, et al., 2012. Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity. Toxicol Appl Pharmacol 264(3):387-394.

Reschke‐Hernández AE, Okerstrom KL, Bowles Edwards A and Tranel D, 2017. Sex and stress: Men and women show different cortisol responses to psychological stress induced by the Trier social stress test and the Iowa singing social stress test. J. Neurosci. Res 95(1-2):106-114.

Rolo AP, Teodoro JS and Palmeira CM, 2012. Role of oxidative stress in the pathogenesis of non-alcoholic steatohepatitis. Free Radic Biol Med 52(1):59-69.

Saikia U, Saikia N, Waters K, et al., 2017. Electronic Properties of Acetaminophen Adsorbed on 2D Clusters: A First Principles Density Functional Study. ChemistrySelect 2(13):3613-3621.

Satapati S, Kucejova B, Duarte JA, et al., 2015. Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. J Clin Invest 125(12):4447.

Schwimmer JB, Dunn W, Norman GJ, et al., 2010. SAFETY study: alanine aminotransferase cutoff values are set too high for reliable detection of pediatric chronic liver disease. Gastroenterology 138(4):1357-1364.

Seal P, Sikdar J, Roy A and Haldar R, 2017. Acetaminophen interacts with human hemoglobin: optical, physical and molecular modeling studies. J Biomol Struct Dyn 35(6):1307-1321.

Sitruk-Ware R, 2006. Mifepristone and misoprostol sequential regimen side effects, complications and safety. Contraception 74(1):48-55.

Spahis S, Delvin E, Borys JM and Levy E, 2017. Oxidative stress as a critical factor in non-alcoholic fatty liver disease pathogenesis. Antioxid. Redox Signal 26(10):519-541.