Author(s): Mahmoud A. Abdel-Monem, Ahmed M. Salem, Karam A. Mahdy, Gamila S. M. El-Saeed, Abdel-Razik H. Farrag, Nahla S. Hassan

Email(s): ,

DOI: 10.52711/0974-360X.2022.00460   

Address: Mahmoud A. Abdel-Monem1*, Ahmed M. Salem2, Karam A. Mahdy1, Gamila S. M. El-Saeed1, Abdel-Razik H. Farrag3, Nahla S. Hassan2
1Department of Medical Biochemistry, National Research Centre, Cairo, Egypt. Postal Code: 12622.
2Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.
3Department of Pathology, National Research Centre, Cairo, Egypt.
*Corresponding Author

Published In:   Volume - 15,      Issue - 6,     Year - 2022

Introduction: Hepatocyte nuclear factors HNF4a and HNF1a, key transcription factors that regulate drug metabolism enzymes expression, were linked to inflammation. Galectin-3 (Gal-3) is a multi-role animal lectin which is involved in inflammation. This study aims to evaluate the impact of galectin-3 inhibition, by using modified citrus pectin (MCP), on HNF4a and HNF1a gene expression levels after acetaminophen (APAP) induced acute liver injury in Wistar rats. Materials and Methods: Sixty-four male Wistar rats were divided into four groups as follows; control, MCP, APAP and MCP plus APAP administered groups. The groups received APAP were divided into three subgroups each; in which rats were sacrificed after 24, 48 and 72 hours (h) from APAP administration. Expression levels of HNF4a and HNF1a, beside levels of Gal-3, tumor necrosis factor- a (TNF-a), Cytochrome P450 2E1 (CYP2E1), reduced glutathione (GSH), glutathione reductase (GR) and peroxidase (GPx) activities, liver function parameters were evaluated, along with histopathological study of the liver. Results: APAP high dose induced inhibition of liver HNF4a and HNF1a gene expression, CYP2E1 and GSH levels, GR and GPx activities, and increased hepatic Gal-3, TNF-a and serum liver function parameters levels, besides inducing hepatic necrosis. The toxic effects were stronger after 24 h then declined gradually after 48 h and 72 h. Inhibiting Gal-3 functionality after APAP high dose administration reduced TNF-a level and retrieved liver levels of HNF4a and HNF1a expression, CYP2E1, GSH, GR and GPx closer to normal control levels. Conclusion: Inhibiting Gal-3 functionality affects HNF4a and HNF1a gene expression levels and reduced inflammation after APAP high dose administration.

Cite this article:
Mahmoud A. Abdel-Monem, Ahmed M. Salem, Karam A. Mahdy, Gamila S. M. El-Saeed, Abdel-Razik H. Farrag, Nahla S. Hassan. Galectin-3 inhibition retained expression of hepatocyte nuclear factors 4α and 1α in acetaminophen induced acute liver injury. Research Journal of Pharmacy and Technology. 2022; 15(6):2747-5. doi: 10.52711/0974-360X.2022.00460

Mahmoud A. Abdel-Monem, Ahmed M. Salem, Karam A. Mahdy, Gamila S. M. El-Saeed, Abdel-Razik H. Farrag, Nahla S. Hassan. Galectin-3 inhibition retained expression of hepatocyte nuclear factors 4α and 1α in acetaminophen induced acute liver injury. Research Journal of Pharmacy and Technology. 2022; 15(6):2747-5. doi: 10.52711/0974-360X.2022.00460   Available on:

1.    Mossanen JC, Tacke F. Acetaminophen-induced acute liver injury in mice. Laboratory Animals. 2015;49(1):30-36. doi: 10.1177/0023677215570992.
2.    Marrone G, Vaccaro FG, Biolato M, Miele L, Liguori A, Araneo C, et al. Drug-induced liver injury 2017: the diagnosis is not easy but always to keep in mind. European Review for Medical Pharmacological Sciences. 2017;21 (1):122-34. PMID: 28379587.
3.    James LP, Mayeux PR, Hinson HA. Acetaminophen-induced hepatotoxicity. Drug Metabolism and Disposition. 2003;31(12):1499-1506. doi: 10.1124/dmd.31.12.1499.
4.    Ilavenil S, Al-Dhabi NA, Srigopalram S, Kim YO, Agastian P, Baru R, et al. Acetaminophen induced hepatotoxicity in Wistar Rats-A proteomic approach. Molecules. 2016;21(2):161-73. doi: 10.3390/molecules21020161.
5.    Cattin A-L, Beyec JL, Barreau F, Saint-Just S, Houllier A, Gonzalez FJ, et al. Hepatocyte nuclear factor 4α, a key factor for homeostasis, cell architecture, and barrier function of the adult intestinal epithelium. Molecular and Cellular Biology. 2009;29(23):6294-308. doi: 10.1128/MCB.00939-09.
6.    Hang H-L, Liu X-Y, Wang H-T, Xu N, Bian J-M, Zhang J-J, et al. Hepatocyte nuclear factor 4A improves hepatic differentiation of immortalized adult human hepatocytes and improves liver function and survival. Experimental Cell Research. 2017;360(2):81-93. doi: 10.1016/j.yexcr.2017.08.020.
7.    Martovetsky G, Tee JB, Nigam SK. Hepatocyte nuclear factors 4α and 1α regulate kidney developmental expression of drug-metabolizing enzymes and drug transporters. Molecular Pharmacology. 2013;84(6):808-23. doi: 10.1124/mol.113.088229.
8.    Meech R, Hu DG, McKinnon RA, Mubarokah SN, Haines AZ, Nair PC, et al. The udp-glycosyltransferase (UGT) superfamily: New members, new functions, and novel paradigms. Physiological Reviews. 2019;99(2):1153-222. doi: 10.1152/physrev.00058.2017.
9.    Li D, Tolleson WH, Yu D, Chen S, Guo L, Xiao W, et al. Regulation of cytochrome P450 expression by microRNAs and long noncoding RNAs: Epigenetic mechanisms in environmental toxicology and carcinogenesis. Journal of Environmental Sciences and Health, Part C, Environmental Carcinogenesis and Ecotoxicological Reviews. 2019;37(3):180-214. doi: 10.1080/10590501.2019.1639481.
10.    Bauzá G, Miller G, Kaseje N, Wang Z, Sherburne A, Agarwal S, et al. Injury-induced changes in liver specific transcription factors hnf-1α and hnf-4α. The Journal of Surgical Research. 2012;175(2):298-304. doi: 10.1016/j.jss.2011.04.062.
11.    Cairo S, Buendia MA. How transient becomes stable: An epigenetic switch linking liver inflammation and tumorigenesis. Journal of Hepatology. 2012;57(4):910-2. doi: 10.1016/j.jhep.2012.05.017.
12.    Babeu J-P, Boudreau F. 2014. Hepatocyte nuclear factor 4-alpha involvement in liver and intestinal inflammatory networks. World Journal of Gastroenterology. 2014;20(1):22-30. doi: 10.3748/wjg.v20.i1.22.
13.    Qian H, Deng D, Huang Z-W, Wei J, Ding C-H, Feng R-X, et al. An HNF1α-regulated feedback circuit modulates hepatic fibrogenesis via the crosstalk between hepatocytes and hepatic stellate cells. Cell Research. 2015;25:930-45. doi: 10.1038/cr.2015.84.
14.    Dragomir A-C, Sun R, Mishin V, Hall LB, Laskin, JD, Laskin DL. Role of galectin-3 in acetaminophen-induced hepatotoxicity and inflammatory mediator production. Toxicological Sciences. 2012;127(2):609-19. doi: 10.1093/toxsci/kfs117.
15.    MacKinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nilsson UJ, Delaine T, et al. Regulation of transforming growth factor-B1-driven lung fibrosis by galectin-3. American Journal of Respiratory and Critical Care Medicine. 2012;185(5):537-46. doi: 10.1164/rccm.201106-0965OC.
16.    Sciacchitano S, Lavra L, Morgante A, Ulivieri A, Magi F, De Francesco GP, et al. Galectin-3: One molecule for an alphabet of diseases, from a to z. International Journal of Molecular Sciences. 2018;19(2):379-438. doi: 10.3390/ijms19020379.
17.    Kolatsi-Joannou M, Price KL, Winyard PJ, Long DA. Modified citrus pectin reduces galectin-3 expression and disease severity in experimental acute kidney injury. PLoS One. 2011;6(4):e18683. doi: 10.1371/journal.pone.0018683.
18.    Zhang T, Lan Y, Zheng Y, Liu F, Zhao D, Mayo KH, et al. Identification of the bioactive components from pH-modified citrus pectin and their inhibitory effects on galectin-3 function. Food Hydrocolloids. 2016;58:113-119. doi: 10.1016/j.foodhyd.2016.02.020.
19.    Reeves BG, Nielsen FH, Fahey GC. AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. The Journal of Nutrition. 1993;123(11):1939-51. doi: 10.1093/jn/123.11.1939.
20.    Dixon MF, Nimmo J, Prescott LF. Experimental paracetamol-induced hepatic Necrosis: A histopathological study. The Journal of Pathology. 1971;103(3):225-9. doi: 10.1002/path.1711030404.
21.    Stone SH. Method for obtaining venous blood from the orbital sinus of the rat or mouse. Science. 1954;119(3081):100. doi: 10.1126/science.119.3081.100.
22.    Bando I, Reus MIS, Andres D, Cascales M. Endogenous Antioxidant Defence System in Rat Liver Following Mercury Chloride Oral Intoxication. Journal of Biochemical and Molecular Toxicology. 2005;19(3):154-61. doi: 10.1002/jbt.20067.
23.    Drury RAB, Wallington EA. Carleton’s histological technique, 4th Edn., Oxford University Press, New York, 1980. pp. 129-40. ISBN: 0192613103.
24.    Armitage P, Berry G, Matthews JNS. Comparison of several groups. Statistical methods in medical research, 4th Edn., Blackwell Scientific Publications, Oxford, 1987. pp. 186-213. ISBN: 0-632-05257-0.
25.    Ozcelik E, Uslu S, Erkasap N, Karimi H. Protective effect of chitosan treatment against acetaminophen-induced hepatotoxicity. Kaohsiung Journal of Medical Sciences. 2014;30(6):286-90. doi: 10.1016/j.kjms.2014.02.003.
26.    Eakins R, Walsh J, Randle L, Jenkins RE, Schuppe-Koistinen I, Rowe C, et al. Adaptation to acetaminophen exposure elicits major changes in expression and distribution of the hepatic proteome. Scientific Reports. 2015; 5(2015):16423-35. doi: 10.1038/srep16423.
27.    Mahmoud YI, Mahmoud AA, Nassar G. Alpha-lipoic acid treatment of acetaminophen-induced rat liver damage. Biotechnic and Histochemistry. 2015;90(8):594-600. doi: 10.3109/10520295.2015.1063005.
28.    Güvenç M, Cellat M, Gökçek İ, Özkan H, Arkalı G, Yakan A, et al. Nobiletin attenuates acetaminophen-induced hepatorenal toxicity in rats. Journal of Biochemical and Molecular Toxicology. 2019;34(2):e22427. doi: 10.1002/jbt.22427.
29.    Kumar HC, Ramesh A, Mohan KG. Hepatoprotective and Antioxidant Effects of Mucuna pruriens Against Acetaminophen-Induced Hepatotoxicity in Albino Wistar Rats. Research J. Pharm. and Tech. 2014;7(1):70-73.
30.    Amin ZA, Bilgen M, Alshawsh MA, Ali HM, Hadi AHA, Abdulla MA. Protective role of Phyllanthus niruri extract against thioacetamide-induced liver cirrhosis in rat model. Evidence-Based Complementary and Alternative Medicine. 2012;2012:241583. doi: 10.1155/2012/241583.
31.    Hinson JA, Roberts DW, James LP. Mechanisms of acetaminophen-induced liver necrosis. Handbook of Experimental Pharmacology. 2010;2010(196):369-405. doi: 10.1007/978-3-642-00663-0_12.
32.    Henderson NC, Mackinnon AC, Rooney C, Sethi T. Galectin-3: A Central Regulator of Chronic Inflammation and Tissue Fibrosis. In: Galectins and Disease Implications for Targeted Therapeutics. Klyosov A, Traber G, Eds., ACS Symposium Series, American Chemical Society, Washington DC, 2012. pp. 377-90. ISBN: 9780841228801.
33.    Li L, Li J, Gao J. Functions of Galectin-3 and Its Role in Fibrotic Diseases. The Journal of Pharmacology and Experimental Therapeutics. 2014;351(2):336-43. doi: 10.1124/jpet.114.218370.
34.    Wang Z, Burke PA. Modulation of hepatocyte nuclear factor-4α function by the peroxisome proliferator- activated receptor-γ co-activator-1α in the acute phase response. The Biochemical Journal. 2008;415(2):289-96. doi: 10.1042/BJ20080355.
35.    Wang Z, Burke PA. Effects of hepatocyte nuclear factor-4α on the regulation of the hepatic acute phase response. Journal of Molecular Biology. 2007;371(2):323-35. doi: 10.1016/j.jmb.2007.05.049.
36.    Papackova Z, Heczkova M, Dankova H, Sticova E, Lodererova A, Bartonova L, et al. Silymarin prevents acetaminophen-induced hepatotoxicity in mice. PLoS ONE. 2018;13(1):e0191353. doi: 10.1371/journal.pone.0191353.
37.    Hakkola J, Hu Y, Ingelman-Sundberg M. Mechanisms of down-regulation of cyp2e1 expression by inflammatory cytokines in rat hepatoma cells. The Journal of Pharmacology and Experimental Therapeutics. 2002;304(3):1048-54. doi: 10.1124/jpet.102.041582.
38.    Groll N, Petrikat T, Vetter S, Colnot S, Weiss F, Poetz O, et al. Coordinate regulation of Cyp2e1 by b-catenin- and hepatocyte nuclear factor 1a-dependent signaling. Toxicology. 2016;350-2:40-48. doi: 10.1016/j.tox.2016.05.004.
39.    Zhang X, Du L, Qiao Y, Zhang X, Zheng W, Wu Q, et al. Ferroptosis is governed by differential regulation of transcription in liver cancer. Redox Biology. 2019;24:101211. doi: 10.1016/j.redox.2019.101211.
40.    Ramirez J, Mirkov S, Zhang W, Chen P, Das S, Liu W, et al. Hepatocyte nuclear factor-1 alpha is associated with UGT1A1, UGT1A9 and UGT2B7 mRNA expression in human liver. The Pharmacogenomics Journal. 2008;8(2):152-61. doi: 10.1038/sj.tpj.6500454.
41.    Hwang-Verslues WW, Sladek FM. HNF4α -- role in drug metabolism and potential drug target? Current Opinion in Pharmacology. 2010;10(6):698-705. doi: 10.1016/j.coph.2010.08.010.
42.    Lu H, Gonzalez FJ, Klaassen C. Alterations in hepatic mRNA expression of phase II enzymes and xenobiotic transporters after targeted disruption of hepatocyte nuclear factor 4 alpha. Toxicological Sciences. 2010;118(2):380-90. doi:10.1093/toxsci/kfq280.
43.    O'Brien PJ, Slaughter MR, Swain A, Birmingham JM, Greenhill RW, Elcock F, et al. Repeated acetaminophen dosing in rats: adaptation of hepatic antioxidant system. Human and Experimental Toxicology. 2000;19(5):277-83. doi: 10.1191/096032700678815918.
44.    Roušar T, Pařík P, Kučera O, Bartoš M, Červinková Z. Glutathione Reductase Is Inhibited by Acetaminophen-glutathione Conjugate In Vitro. Physiological Research. 2010;59(2):225-32. doi: 10.33549/physiolres.931744.
45.    Marcil V, Seidman E, Sinnett D, Boudreau F, Gendron F-P, Beaulieu J-F, et al. Modification in oxidative stress, inflammation, and lipoprotein assembly in response to hepatocyte nuclear factor 4α knockdown in intestinal epithelial cells. The Journal of Biological Chemistry. 2010;285(52):40448-60. doi: 10.1074/jbc.M110.155358.

Recomonded Articles:

Research Journal of Pharmacy and Technology (RJPT) is an international, peer-reviewed, multidisciplinary journal.... Read more >>>

RNI: CHHENG00387/33/1/2008-TC                     
DOI: 10.5958/0974-360X 

56th percentile
Powered by  Scopus

SCImago Journal & Country Rank

Recent Articles


Not Available