Therapeutic Potential of Nutraceuticals against Drug-Induced Liver Injury

Abstract

Drug-induced liver injury (DILI) continues to be a major concern in clinical practice, thus necessitating a need for novel therapeutic approaches to alleviate its impact on hepatic function. This review investigates the therapeutic potential of nutraceuticals against DILI, focusing on examining the underlying molecular mechanisms and cellular pathways. In preclinical and clinical studies, nutraceuticals, such as silymarin, curcumin, and N-acetylcysteine, have demonstrated remarkable efficacy in attenuating liver injury induced by diverse pharmaceutical agents. The molecular mechanisms underlying these hepatoprotective effects involve modulation of oxidative stress, inflammation, and apoptotic pathways. Furthermore, this review examines cellular routes affected by these nutritional components focusing on their influence on hepatocytes, Kupffer cells, and stellate cells. Key evidence highlights that autophagy modulation as well as unfolded protein response are essential cellular processes through which nutraceuticals exert their cytoprotective functions. In conclusion, nutraceuticals are emerging as promising therapeutic agents for mitigating DILI, by targeting different molecular pathways along with cell processes involved in it concurrently.

Keywords

drug-induced liver injury - polyphenols - terpenes - Nrf-2 - oxidative stress

Authors' Contributions

N.S. conceptualized and wrote the manuscript. M.K. edited the manuscript and prepared the figures and tables. M.M. wrote and edited the manuscript. Y.B. wrote and edited the manuscript. A.M. edited the manuscript. S.T. edited the manuscript. M.R. edited the manuscript. M.B. conceptualized, wrote, and edited the manuscript.

Publication History

Article published online:
11 October 2024

• References

• 1 Lee WM. Drug-induced acute liver failure. Clin Liver Dis 2013; 17 (04) 575-586 , viii
• 2 Miguel A, Azevedo LF, Araújo M, Pereira AC. Frequency of adverse drug reactions in hospitalized patients: a systematic review and meta-analysis. Pharmacoepidemiol Drug Saf 2012; 21 (11) 1139-1154
• 3 Lee WM. Acetaminophen (APAP) hepatotoxicity - Isn't it time for APAP to go away?. J Hepatol 2017; 67 (06) 1324-1331
• 4 Ostapowicz G, Fontana RJ, Schiødt FV. et al; U.S. Acute Liver Failure Study Group. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137 (12) 947-954
• 5 Bernal W, Wendon J. Acute liver failure. N Engl J Med 2013; 369 (26) 2525-2534
• 6 CIOMS Working Group on Drug-induced liver injury (DILI).. Drug-induced liver injury (DILI): current status and future directions for drug development and the post-market setting. Council Int Organizations Med Sci 2020
• 7 Datta S, Aggarwal D, Sehrawat N. et al. Hepatoprotective effects of natural drugs: current trends, scope, relevance and future perspectives. Phytomedicine 2023; 121: 155100
• 8 Rani J, Dhull SB, Rose PK, Kidwai MK. Drug-induced liver injury and anti-hepatotoxic effect of herbal compounds: a metabolic mechanism perspective. Phytomedicine 2024; 122: 155142
• 9 Simón J, Casado-Andrés M, Goikoetxea-Usandizaga N, Serrano-Maciá M, Martínez-Chantar ML. Nutraceutical properties of polyphenols against liver diseases. Nutrients 2020; 12 (11) 3517
• 10 Young IS, Woodside JV. Antioxidants in health and disease. J Clin Pathol 2001; 54 (03) 176-186
• 11 Lobo V, Patil A, Phatak A, Chandra N. Free radicals, antioxidants and functional foods: impact on human health. Pharmacogn Rev 2010; 4 (08) 118-126
• 12 Ronis MJJ, Pedersen KB, Watt J. Adverse effects of nutraceuticals and dietary supplements. Annu Rev Pharmacol Toxicol 2018; 58 (01) 583-601
• 13 Villanueva-Paz M, Morán L, López-Alcántara N. et al. Oxidative stress in drug-induced liver injury (DILI): from mechanisms to biomarkers for use in clinical practice. Antioxidants 2021; 10 (03) 390
• 14 Pan Y, Tang P, Cao J. et al. Lipid peroxidation aggravates anti-tuberculosis drug-induced liver injury: evidence of ferroptosis induction. Biochem Biophys Res Commun 2020; 533 (04) 1512-1518
• 15 Walgren JL, Mitchell MD, Thompson DC. Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit Rev Toxicol 2005; 35 (04) 325-361
• 16 Huang JH, Zhang C, Zhang DG, Li L, Chen X, Xu DX. Rifampicin-induced hepatic lipid accumulation: association with up-regulation of peroxisome proliferator-activated receptor γ in mouse liver. PLoS One 2016; 11 (11) e0165787
• 17 Ngo V, Duennwald ML. Nrf2 and oxidative stress: a general overview of mechanisms and implications in human disease. Antioxidants 2022; 11 (12) 2345
• 18 Li S, Tan HY, Wang N. et al. The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci 2015; 16 (11) 26087-26124
• 19 Xiao Y, Kim M, Lazar MA. Nuclear receptors and transcriptional regulation in non-alcoholic fatty liver disease. Mol Metab 2021; 50: 101119
• 20 Barretto SA, Lasserre F, Fougerat A. et al. Gene expression profiling reveals that PXR activation inhibits hepatic PPARα activity and decreases FGF21 secretion in male C57Bl6/J Mice. Int J Mol Sci 2019; 20 (15) 3767
• 21 Kim JH, Nam WS, Kim SJ. et al. Mechanism investigation of rifampicin-induced liver injury using comparative toxicoproteomics in mice. Int J Mol Sci 2017; 18 (07) 1417
• 22 Moore M, Thor H, Moore G, Nelson S, Moldéus P, Orrenius S. The toxicity of acetaminophen and N-acetyl-p-benzoquinone imine in isolated hepatocytes is associated with thiol depletion and increased cytosolic Ca2+. J Biol Chem 1985; 260 (24) 13035-13040
• 23 Poli G, Albano E, Dianzani MU. The role of lipid peroxidation in liver damage. Chem Phys Lipids 1987; 45 (2-4): 117-142
• 24 Almazroo OA, Miah MK, Venkataramanan R. Drug metabolism in the liver. Clin Liver Dis 2017; 21 (01) 1-20
• 25 Rushmore TH, Morton MR, Pickett CB. The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem 1991; 266 (18) 11632-11639
• 26 Itoh K, Chiba T, Takahashi S. et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 1997; 236 (02) 313-322
• 27 Pamplona R, Costantini D. Molecular and structural antioxidant defenses against oxidative stress in animals. Am J Physiol Regul Integr Comp Physiol 2011; 301 (04) R843-R863
• 28 He L, He T, Farrar S, Ji L, Liu T, Ma X. Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species. Cell Physiol Biochem 2017; 44 (02) 532-553
• 29 Conde De La Rosa L, Goicoechea L, Torres S, Garcia-Ruiz C, Fernandez-Checa JC. Role of oxidative stress in liver disorders. Livers 2022; 2 (04) 283-314
• 30 Linares V, Alonso V, Albina ML. et al. Lipid peroxidation and antioxidant status in kidney and liver of rats treated with sulfasalazine. Toxicology 2009; 256 (03) 152-156
• 31 Karabulut AB, Gül M, Karabulut E, Kiran TR, Ocak SG, Otlu O. Oxidant and antioxidant activity in rabbit livers treated with zoledronic acid. Transplant Proc 2010; 42 (09) 3820-3822
• 32 Videla LA. Oxidative stress signaling underlying liver disease and hepatoprotective mechanisms. World J Hepatol 2009; 1 (01) 72-78
• 33 Zhang YKJ, Wu KC, Klaassen CD. Genetic activation of Nrf2 protects against fasting-induced oxidative stress in livers of mice. PLoS One. 2013; 8 (03) e59122
• 34 Klaassen CD, Reisman SA. Nrf2 the rescue: effects of the antioxidative/electrophilic response on the liver. Toxicol Appl Pharmacol 2010; 244 (01) 57-65
• 35 Tang W, Jiang YF, Ponnusamy M, Diallo M. Role of Nrf2 in chronic liver disease. World J Gastroenterol 2014; 20 (36) 13079-13087
• 36 Kwak MK, Kensler TW. Targeting NRF2 signaling for cancer chemoprevention. Toxicol Appl Pharmacol 2010; 244 (01) 66-76
• 37 Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 2014; 39 (04) 199-218
• 38 Ye H, Nelson LJ, Gómez Del Moral M, Martínez-Naves E, Cubero FJ. Dissecting the molecular pathophysiology of drug-induced liver injury. World J Gastroenterol 2018; 24 (13) 1373-1385
• 39 Nadanaciva S, Dykens JA, Bernal A, Capaldi RA, Will Y. Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration. Toxicol Appl Pharmacol 2007; 223 (03) 277-287
• 40 Levy RH, Rettenmeier AW, Anderson GD. et al. Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4-ene-valproate, a hepatotoxic metabolite of valproic acid. Clin Pharmacol Ther 1990; 48 (03) 225-235
• 41 Scharman EJ. Amiodarone. In: Encyclopedia of Toxicology. Elsevier;; 2005: 98-99
• 42 Perry EA, Bennett CF, Luo C. et al. Tetracyclines promote survival and fitness in mitochondrial disease models. Nat Metab 2021; 3 (01) 33-42
• 43 Pessayre D, Fromenty B, Berson A. et al. Central role of mitochondria in drug-induced liver injury. Drug Metab Rev 2012; 44 (01) 34-87
• 44 Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol 2007; 35 (04) 495-516
• 45 Waterhouse NJ, Goldstein JC, von Ahsen O, Schuler M, Newmeyer DD, Green DR. Cytochrome c maintains mitochondrial transmembrane potential and ATP generation after outer mitochondrial membrane permeabilization during the apoptotic process. J Cell Biol 2001; 153 (02) 319-328
• 46 Morris AAM. Mitochondrial respiratory chain disorders and the liver. Liver 1999; 19 (05) 357-368
• 47 Zhou Y, Jing S, Liu S. et al. Double-activation of mitochondrial permeability transition pore opening via calcium overload and reactive oxygen species for cancer therapy. J Nanobiotechnology 2022; 20 (01) 188
• 48 Ramachandran A, Umbaugh DS, Jaeschke H. Mitochondrial dynamics in drug-induced liver injury. Livers 2021; 1 (03) 102-115
• 49 Liang Q, Zeng J, Wu J. et al. Nucleoside reverse transcriptase inhibitors induced hepatocellular mitochondrial DNA lesions and compensatory enhancement of mitochondrial function and DNA repair. Int J Antimicrob Agents 2018; 51 (03) 385-392
• 50 Hangas A, Aasumets K, Kekäläinen NJ. et al. Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2. Nucleic Acids Res 2018; 46 (18) 9625-9636
• 51 Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol 2007; 49 (23) 2231-2237
• 52 Fromenty B. Inhibition of mitochondrial fatty acid oxidation in drug-induced hepatic steatosis. Liver Res 2019; 3 (3–4): 157-169
• 53 Zhou S, Palmeira CM, Wallace KB. Doxorubicin-induced persistent oxidative stress to cardiac myocytes. Toxicol Lett 2001; 121 (03) 151-157
• 54 Hetz C, Papa FR. The unfolded protein response and cell fate control. Mol Cell 2018; 69 (02) 169-181
• 55 Uzi D, Barda L, Scaiewicz V. et al. CHOP is a critical regulator of acetaminophen-induced hepatotoxicity. J Hepatol 2013; 59 (03) 495-503
• 56 Fredriksson L, Wink S, Herpers B. et al. Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNFα-mediated hepatotoxicity. Toxicol Sci 2014; 140 (01) 144-159
• 57 Wu J, Chen S, Liu H. et al. Tunicamycin specifically aggravates ER stress and overcomes chemoresistance in multidrug-resistant gastric cancer cells by inhibiting N-glycosylation. J Exp Clin Cancer Res 2018; 37 (01) 272
• 58 Longas MO, Kotapati A, Prasad KP. et al. Balancing life with glycoconjugates: monitoring unfolded protein response-mediated anti-angiogenic action of tunicamycin by Raman Spectroscopy. Pure Appl Chem 2012; 84 (09) 1907-1918
• 59 Jiang J, Briedé JJ, Jennen DGJ. et al. Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett 2015; 234 (02) 139-150
• 60 Lee HJ, Oh YK, Rhee M. et al. The role of STAT1/IRF-1 on synergistic ROS production and loss of mitochondrial transmembrane potential during hepatic cell death induced by LPS/d-GalN. J Mol Biol 2007; 369 (04) 967-984
• 61 Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc 2014; 89 (01) 95-106
• 62 Singh R, Czaja MJ. Regulation of hepatocyte apoptosis by oxidative stress. J Gastroenterol Hepatol 2007; 22 (Suppl. 01) S45-S48
• 63 Veith A, Moorthy B. Role of cytochrome P450s in the generation and metabolism of reactive oxygen species. Curr Opin Toxicol 2018; 7: 44-51
• 64 Lee SST, Buters JTM, Pineau T, Fernandez-Salguero P, Gonzalez FJ. Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem 1996; 271 (20) 12063-12067
• 65 Kumar S, Singla B, Singh AK, Thomas-Gooch SM, Zhi K, Singh UP. Hepatic, extrahepatic and extracellular vesicle cytochrome P450 2E1 in alcohol and acetaminophen-mediated adverse interactions and potential treatment options. Cells 2022; 11 (17) 2620
• 66 Kučera O, Endlicher R, Roušar T. et al. The effect of tert-butyl hydroperoxide-induced oxidative stress on lean and steatotic rat hepatocytes in vitro. Oxid Med Cell Longev 2014; 2014: 752506
• 67 Jones BE, Liu H, Lo CR, Koop DR, Czaja MJ. Cytochrome P450 2E1 expression induces hepatocyte resistance to cell death from oxidative stress. Antioxid Redox Signal 2002; 4 (05) 701-709
• 68 Huang YS, Chern HD, Su WJ. et al. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology 2003; 37 (04) 924-930
• 69 Harjumäki R, Pridgeon CS, Ingelman-Sundberg M. CYP2E1 in alcoholic and non-alcoholic liver injury. Roles of ROS, reactive intermediates and lipid overload. Int J Mol Sci 2021; 22 (15) 8221
• 70 Regulation of xenobiotic and bile acid metabolism by the nuclear pregnane X receptor - Journal of Lipid Research. Accessed August 8, 2024 at: https://www.jlr.org/article/S0022-2275(20)30141-3/fulltext
• 71 Goodwin B, Hodgson E, Liddle C. The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol Pharmacol 1999; 56 (06) 1329-1339
• 72 Iorga A, Dara L, Kaplowitz N. Drug-induced liver injury: cascade of events leading to cell death, apoptosis or necrosis. Int J Mol Sci 2017; 18 (05) 1018
• 73 Martin-Murphy BV, Holt MP, Ju C. The role of damage associated molecular pattern molecules in acetaminophen-induced liver injury in mice. Toxicol Lett 2010; 192 (03) 387-394
• 74 Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways. Nat Cell Biol 2001; 3 (11) E255-E263
• 75 Voican CS, Corruble E, Naveau S, Perlemuter G. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry 2014; 171 (04) 404-415
• 76 Todorović Vukotić N, Đorđević J, Pejić S, Đorđević N, Pajović SB. Antidepressants- and antipsychotics-induced hepatotoxicity. Arch Toxicol 2021; 95 (03) 767-789
• 77 Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 2010; 11 (10) 700-714
• 78 Suda J, Dara L, Yang L. et al. Knockdown of RIPK1 markedly exacerbates murine immune-mediated liver injury through massive apoptosis of hepatocytes, independent of necroptosis and inhibition of NF-κB. J Immunol 2016; 197 (08) 3120-3129
• 79 Remijsen Q, Goossens V, Grootjans S. et al. Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis. Cell Death Dis 2014; 5 (01) e1004-e1004
• 80 Tischer S, Fontana RJ. Drug-drug interactions with oral anti-HCV agents and idiosyncratic hepatotoxicity in the liver transplant setting. J Hepatol 2014; 60 (04) 872-884
• 81 Ju C, Reilly T. Role of immune reactions in drug-induced liver injury (DILI). Drug Metab Rev 2012; 44 (01) 107-115
• 82 Padovan E, Bauer T, Tongio MM, Kalbacher H, Weltzien HU. Penicilloyl peptides are recognized as T cell antigenic determinants in penicillin allergy. Eur J Immunol 1997; 27 (06) 1303-1307
• 83 Watkins S, Pichler WJ. Sulfamethoxazole induces a switch mechanism in T cell receptors containing TCRVβ20–1, altering pHLA recognition. PLoS One 2013; 8 (10) e76211
• 84 Nicoletti P, Aithal GP, Bjornsson ES. et al; International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium. Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a genome-wide association study. Gastroenterology 2017; 152 (05) 1078-1089
• 85 Gerussi A, Natalini A, Antonangeli F. et al. Immune-mediated drug-induced liver injury: immunogenetics and experimental models. Int J Mol Sci 2021; 22 (09) 4557
• 86 Heidari R, Niknahad H, Jamshidzadeh A, Eghbal MA, Abdoli N. An overview on the proposed mechanisms of antithyroid drugs-induced liver injury. Adv Pharm Bull. Published online 2015;
• 87 Devarbhavi H, Andrade RJ. Drug-induced liver injury due to antimicrobials, central nervous system agents, and nonsteroidal anti-inflammatory drugs. Semin Liver Dis 2014; 34 (02) 145-161
• 88 Kuna L, Bozic I, Kizivat T. et al. Models of drug induced liver injury (DILI) - current issues and future perspectives. Curr Drug Metab 2018; 19 (10) 830-838
• 89 Li X, Ni J, Chen L. Advances in the study of acetaminophen-induced liver injury. Front Pharmacol 2023; 14: 1239395
• 90 Allegaert K, van den Anker JN. Perinatal and neonatal use of paracetamol for pain relief. Semin Fetal Neonatal Med 2017; 22 (05) 308-313
• 91 Mazaleuskaya LL, Sangkuhl K, Thorn CF, FitzGerald GA, Altman RB, Klein TE. PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics 2015; 25 (08) 416-426
• 92 Jan YH, Heck DE, Dragomir AC, Gardner CR, Laskin DL, Laskin JD. Acetaminophen reactive intermediates target hepatic thioredoxin reductase. Chem Res Toxicol 2014; 27 (05) 882-894
• 93 Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 2007; 87 (01) 315-424
• 94 Xiao Q, Zhao Y, Ma L, Piao R. Orientin reverses acetaminophen-induced acute liver failure by inhibiting oxidative stress and mitochondrial dysfunction. J Pharmacol Sci 2022; 149 (01) 11-19
• 95 Lee SK, Bae GH, Kim YS. et al. A phospholipase D2 inhibitor, CAY10594, ameliorates acetaminophen-induced acute liver injury by regulating the phosphorylated-GSK-3β/JNK axis. Sci Rep 2019; 9 (01) 7242
• 96 Petrov PD, Soluyanova P, Sánchez-Campos S, Castell JV, Jover R. Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: role of NRF2 and FXR pathways. Food Chem Toxicol 2021; 158: 112664
• 97 Lucena MI, Andrade RJ, Fernández MC. et al; Spanish Group for the Study of Drug-Induced Liver Disease (Grupo de Estudio para las Hepatopatías Asociadas a Medicamentos (GEHAM)). Determinants of the clinical expression of amoxicillin-clavulanate hepatotoxicity: a prospective series from Spain. Hepatology 2006; 44 (04) 850-856
• 98 Andrade RJ, Lucena MI, Fernández MC. et al; Spanish Group for the Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005; 129 (02) 512-521
• 99 Lucena MI, Molokhia M, Shen Y. et al; Spanish DILI Registry, EUDRAGENE, DILIN, DILIGEN, International SAEC. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology 2011; 141 (01) 338-347
• 100 Poulsen KL, Albee RP, Ganey PE, Roth RA. Trovafloxacin potentiation of lipopolysaccharide-induced tumor necrosis factor release from RAW 264.7 cells requires extracellular signal-regulated kinase and c-Jun N-Terminal Kinase. J Pharmacol Exp Ther 2014; 349 (02) 185-191
• 101 Shaw PJ, Ganey PE, Roth RA. Trovafloxacin enhances the inflammatory response to a Gram-negative or a Gram-positive bacterial stimulus, resulting in neutrophil-dependent liver injury in mice. J Pharmacol Exp Ther 2009; 330 (01) 72-78
• 102 Agal S, Baijal R, Pramanik S. et al. Monitoring and management of antituberculosis drug induced hepatotoxicity. J Gastroenterol Hepatol 2005; 20 (11) 1745-1752
• 103 Saukkonen JJ, Cohn DL, Jasmer RM. et al; ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Subcommittee. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006; 174 (08) 935-952
• 104 Younossian AB, Rochat T, Ketterer JP, Wacker J, Janssens JP. High hepatotoxicity of pyrazinamide and ethambutol for treatment of latent tuberculosis. Eur Respir J 2005; 26 (03) 462-464
• 105 Papastavros T, Dolovich LR, Holbrook A, Whitehead L, Loeb M. Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis. CMAJ 2002; 167 (02) 131-136
• 106 Metushi I, Uetrecht J, Phillips E. Mechanism of isoniazid-induced hepatotoxicity: then and now. Br J Clin Pharmacol 2016; 81 (06) 1030-1036
• 107 Nicoletti P, Devarbhavi H, Goel A. et al. Genetic risk factors in drug-induced liver injury due to isoniazid-containing antituberculosis drug regimens. Clin Pharmacol Ther 2021; 109 (04) 1125-1135
• 108 Ezhilarasan D. Hepatotoxic potentials of methotrexate: understanding the possible toxicological molecular mechanisms. Toxicology 2021; 458: 152840
• 109 Kobayashi K, Terada C, Tsukamoto I. Methotrexate-induced apoptosis in hepatocytes after partial hepatectomy. Eur J Pharmacol 2002; 438 (1-2): 19-24
• 110 Han D, Dara L, Win S. et al. Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria. Trends Pharmacol Sci 2013; 34 (04) 243-253
• 111 Björnsson ES, Gunnarsson BI, Gröndal G. et al. Risk of drug-induced liver injury from tumor necrosis factor antagonists. Clin Gastroenterol Hepatol 2015; 13 (03) 602-608
• 112 Meseguer ES, Elizalde MU, Borobia AM, Ramírez E. Valproic acid-induced liver injury: a case-control study from a prospective pharmacovigilance program in a tertiary hospital. J Clin Med 2021; 10 (06) 1153
• 113 Gayam V, Mandal AK, Khalid M, Shrestha B, Garlapati P, Khalid M. Valproic acid induced acute liver injury resulting in hepatic encephalopathy - a case report and literature review. J Community Hosp Intern Med Perspect 2018; 8 (05) 311-314
• 114 Silva MFB, Ruiter JPN, Illst L. et al. Valproate inhibits the mitochondrial pyruvate-driven oxidative phosphorylation in vitro. J Inherit Metab Dis 1997; 20 (03) 397-400
• 115 Girish C, Sanjay S. Role of immune dysfunction in drug induced liver injury. World J Hepatol 2021; 13 (11) 1677-1687
• 116 Kurth MJ, Yokoi T, Gershwin ME. Halothane-induced hepatitis: paradigm or paradox for drug-induced liver injury. Hepatology 2014; 60 (05) 1473-1475
• 117 Kalra EK. Nutraceutical -- definition and introduction. AAPS PharmSci 2003; 5 (03) E25
• 118 Nasri H, Baradaran A, Shirzad H, Rafieian-Kopaei M. New concepts in nutraceuticals as alternative for pharmaceuticals. Int J Prev Med 2014; 5 (12) 1487-1499
• 119 Ricordi C, Garcia-Contreras M, Farnetti S. Diet and inflammation: possible effects on immunity, chronic diseases, and life span. J Am Coll Nutr 2015; 34 (1, Suppl 1): 10-13
• 120 Das L, Bhaumik E, Raychaudhuri U, Chakraborty R. Role of nutraceuticals in human health. J Food Sci Technol 2012; 49 (02) 173-183
• 121 Osna NA, Donohue Jr TM, Kharbanda KK. Alcoholic liver disease: pathogenesis and current management. Alcohol Res 2017; 38 (02) 147-161
• 122 AlAli M, Alqubaisy M, Aljaafari MN. et al. Nutraceuticals: transformation of conventional foods into health promoters/disease preventers and safety considerations. Molecules 2021; 26 (09) 2540
• 123 Frank J, Eliasson C, Leroy-Nivard D. et al. Dietary secoisolariciresinol diglucoside and its oligomers with 3-hydroxy-3-methyl glutaric acid decrease vitamin E levels in rats. Br J Nutr 2004; 92 (01) 169-176
• 124 Shi Z, Wu J, Yang Q, Xia H, Deng M, Yang Y. Efficacy and safety of milk thistle preventive treatment of anti-tuberculosis drug-induced liver injury: a protocol for systematic review and meta-analysis. Medicine (Baltimore) 2020; 99 (52) e23674
• 125 Sanabria-Cabrera J, Tabbai S, Niu H. et al. N-acetylcysteine for the management of non-acetaminophen drug-induced liver injury in adults: a systematic review. Front Pharmacol 2022; 13: 876868
• 126 Li AN, Li S, Zhang YJ, Xu XR, Chen YM, Li HB. Resources and biological activities of natural polyphenols. Nutrients 2014; 6 (12) 6020-6047
• 127 Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr 2004; 79 (05) 727-747
• 128 Hosseinian FS, Beta T. Saskatoon and wild blueberries have higher anthocyanin contents than other Manitoba berries. J Agric Food Chem 2007; 55 (26) 10832-10838
• 129 Davinelli S, Bertoglio JC, Zarrelli A, Pina R, Scapagnini G. A randomized clinical trial evaluating the efficacy of an anthocyanin-maqui berry extract (Delphinol®) on oxidative stress biomarkers. J Am Coll Nutr 2015; 34 (1, Suppl 1): 28-33
• 130 Park S, Kang S, Jeong DY, Jeong SY, Park JJ, Yun HS. Cyanidin and malvidin in aqueous extracts of black carrots fermented with Aspergillus oryzae prevent the impairment of energy, lipid and glucose metabolism in estrogen-deficient rats by AMPK activation. Genes Nutr 2015; 10 (02) 455
• 131 Bendia E, Benedetti A, Baroni GS. et al. Effect of cyanidin 3-O-β-glucopyranoside on hepatic stellate cell proliferation and collagen synthesis induced by oxidative stress. Dig Liver Dis 2005; 37 (05) 342-348
• 132 Jaramillo Flores ME. Cocoa flavanols: natural agents with attenuating effects on metabolic syndrome risk factors. Nutrients 2019; 11 (04) 751
• 133 Cheng H, Xu N, Zhao W. et al. (-)-Epicatechin regulates blood lipids and attenuates hepatic steatosis in rats fed high-fat diet. Mol Nutr Food Res 2017; 61 (11) 1700303
• 134 Dower JI, Geleijnse JM, Kroon PA. et al. Does epicatechin contribute to the acute vascular function effects of dark chocolate? A randomized, crossover study. Mol Nutr Food Res 2016; 60 (11) 2379-2386
• 135 Huang Z, Jing X, Sheng Y. et al. (-)-Epicatechin attenuates hepatic sinusoidal obstruction syndrome by inhibiting liver oxidative and inflammatory injury. Redox Biol 2019; 22: 101117
• 136 Chen C, Liu Q, Liu L, Hu YY, Feng Q. Potential biological effects of (-)-epigallocatechin-3-gallate on the treatment of nonalcoholic fatty liver disease. Mol Nutr Food Res 2018; 62 (01) 1700483
• 137 Yao HT, Li CC, Chang CH. Epigallocatechin-3-gallate reduces hepatic oxidative stress and lowers CYP-mediated bioactivation and toxicity of acetaminophen in rats. Nutrients 2019; 11 (08) 1862
• 138 Dai N, Zou Y, Zhu L, Wang HF, Dai MG. Antioxidant properties of proanthocyanidins attenuate carbon tetrachloride (CCl4)-induced steatosis and liver injury in rats via CYP2E1 regulation. J Med Food 2014; 17 (06) 663-669
• 139 Ooghe WC, Detavernier CM. Detection of the addition of Citrus reticulata and hybrids to Citrus sinensis by flavonoids. J Agric Food Chem 1997; 45 (05) 1633-1637
• 140 Pari L, Karthikeyan A, Karthika P, Rathinam A. Protective effects of hesperidin on oxidative stress, dyslipidaemia and histological changes in iron-induced hepatic and renal toxicity in rats. Toxicol Rep 2014; 2: 46-55
• 141 Ahmed OM, Fahim HI, Ahmed HY. et al. The preventive effects and the mechanisms of action of navel orange peel hydroethanolic extract, naringin, and naringenin in N-acetyl-p-aminophenol-induced liver injury in Wistar rats. Oxid Med Cell Longev 2019; 2019: 2745352
• 142 Hernández-Aquino E, Muriel P. Beneficial effects of naringenin in liver diseases: molecular mechanisms. World J Gastroenterol 2018; 24 (16) 1679-1707
• 143 Li Y, Yao J, Han C. et al. Quercetin, inflammation and immunity. Nutrients 2016; 8 (03) 167
• 144 Chen X. Protective effects of quercetin on liver injury induced by ethanol. Pharmacogn Mag 2010; 6 (22) 135-141
• 145 Somerset SM, Johannot L. Dietary flavonoid sources in Australian adults. Nutr Cancer 2008; 60 (04) 442-449
• 146 Ganbold M, Owada Y, Ozawa Y. et al. Isorhamnetin alleviates steatosis and fibrosis in mice with nonalcoholic steatohepatitis. Sci Rep 2019; 9 (01) 16210
• 147 Igarashi K, Ohmuma M. Effects of isorhamnetin, rhamnetin, and quercetin on the concentrations of cholesterol and lipoperoxide in the serum and liver and on the blood and liver antioxidative enzyme activities of rats. Biosci Biotechnol Biochem 1995; 59 (04) 595-601
• 148 Yang JH, Kim SC, Kim KM. et al. Isorhamnetin attenuates liver fibrosis by inhibiting TGF-β/Smad signaling and relieving oxidative stress. Eur J Pharmacol 2016; 783: 92-102
• 149 Hostetler GL, Ralston RA, Schwartz SJ. Flavones: food sources, bioavailability, metabolism, and bioactivity. Adv Nutr 2017; 8 (03) 423-435
• 150 Wang F, Liu JC, Zhou RJ. et al. Apigenin protects against alcohol-induced liver injury in mice by regulating hepatic CYP2E1-mediated oxidative stress and PPARα-mediated lipogenic gene expression. Chem Biol Interact 2017; 275: 171-177
• 151 Tsaroucha AK, Tsiaousidou A, Ouzounidis N. et al. Intraperitoneal administration of apigenin in liver ischemia/reperfusion injury protective effects. Saudi J Gastroenterol 2016; 22 (06) 415-422
• 152 Jung UJ, Cho YY, Choi MS. Apigenin ameliorates dyslipidemia, hepatic steatosis and insulin resistance by modulating metabolic and transcriptional profiles in the liver of high-fat diet-induced obese mice. Nutrients 2016; 8 (05) 305
• 153 Pai SA, Munshi RP, Panchal FH, Gaur IS, Juvekar AR. Chrysin ameliorates nonalcoholic fatty liver disease in rats. Naunyn Schmiedebergs Arch Pharmacol 2019; 392 (12) 1617-1628
• 154 Tai M, Zhang J, Song S. et al. Protective effects of luteolin against acetaminophen-induced acute liver failure in mouse. Int Immunopharmacol 2015; 27 (01) 164-170
• 155 Lin Y, Shi R, Wang X, Shen HM. Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets 2008; 8 (07) 634-646
• 156 Xin X, Chen C, Hu YY, Feng Q. Protective effect of genistein on nonalcoholic fatty liver disease (NAFLD). Biomed Pharmacother 2019; 117: 109047
• 157 Kuzu N, Metin K, Dagli AF. et al. Protective role of genistein in acute liver damage induced by carbon tetrachloride. Mediators Inflamm 2007; 2007: 36381
• 158 Yin Y, Liu H, Zheng Z, Lu R, Jiang Z. Genistein can ameliorate hepatic inflammatory reaction in nonalcoholic steatohepatitis rats. Biomed Pharmacother 2019; 111: 1290-1296
• 159 Kim MH, Park JS, Jung JW, Byun KW, Kang KS, Lee YS. Daidzein supplementation prevents non-alcoholic fatty liver disease through alternation of hepatic gene expression profiles and adipocyte metabolism. Int J Obes (Lond) 2011; 35 (08) 1019-1030
• 160 Takahashi Y, Odbayar TO, Ide T. A comparative analysis of genistein and daidzein in affecting lipid metabolism in rat liver. J Clin Biochem Nutr 2009; 44 (03) 223-230
• 161 Kumar N, Goel N. Phenolic acids: natural versatile molecules with promising therapeutic applications. Biotechnol Rep (Amst) 2019; 24: e00370
• 162 Chen P, Chen F, Zhou B. Antioxidative, anti-inflammatory and anti-apoptotic effects of ellagic acid in liver and brain of rats treated by D-galactose. Sci Rep 2018; 8 (01) 1465
• 163 Aslan A, Gok O, Erman O, Kuloglu T. Ellagic acid impedes carbontetrachloride-induced liver damage in rats through suppression of NF-kB, Bcl-2 and regulating Nrf-2 and caspase pathway. Biomed Pharmacother 2018; 105: 662-669
• 164 Kapan M, Gumus M, Onder A. et al. The effects of ellagic acid on the liver and remote organs' oxidative stress and structure after hepatic ischemia reperfusion injury caused by pringle maneuver in rats. Bratisl Lek Listy 2012; 113 (05) 274-281
• 165 Rasool MK, Sabina EP, Ramya SR. et al. Hepatoprotective and antioxidant effects of gallic acid in paracetamol-induced liver damage in mice. J Pharm Pharmacol 2010; 62 (05) 638-643
• 166 Bayramoglu G, Kurt H, Bayramoglu A, Gunes HV, Degirmenci İ, Colak S. Preventive role of gallic acid on hepatic ischemia and reperfusion injury in rats. Cytotechnology 2015; 67 (05) 845-849
• 167 Mahmoud AM, Hussein OE, Hozayen WG, Bin-Jumah M, Abd El-Twab SM. Ferulic acid prevents oxidative stress, inflammation, and liver injury via upregulation of Nrf2/HO-1 signaling in methotrexate-induced rats. Environ Sci Pollut Res Int 2020; 27 (08) 7910-7921
• 168 Shi H, Dong L, Jiang J. et al. Chlorogenic acid reduces liver inflammation and fibrosis through inhibition of toll-like receptor 4 signaling pathway. Toxicology 2013; 303: 107-114
• 169 Kim H, Pan JH, Kim SH, Lee JH, Park JW. Chlorogenic acid ameliorates alcohol-induced liver injuries through scavenging reactive oxygen species. Biochimie 2018; 150: 131-138
• 170 Barbaro B, Toietta G, Maggio R. et al. Effects of the olive-derived polyphenol oleuropein on human health. Int J Mol Sci 2014; 15 (10) 18508-18524
• 171 Park S, Choi Y, Um SJ, Yoon SK, Park T. Oleuropein attenuates hepatic steatosis induced by high-fat diet in mice. J Hepatol 2011; 54 (05) 984-993
• 172 Jemai H, Mahmoudi A, Feryeni A. et al. Hepatoprotective effect of oleuropein-rich extract from olive leaves against cadmium-induced toxicity in mice. BioMed Res Int 2020; 2020: 4398924
• 173 Maiti P, Dunbar GL. Use of curcumin, a natural polyphenol for targeting molecular pathways in treating age-related neurodegenerative diseases. Int J Mol Sci 2018; 19 (06) 1637
• 174 Farzaei MH, Zobeiri M, Parvizi F. et al. Curcumin in liver diseases: a systematic review of the cellular mechanisms of oxidative stress and clinical perspective. Nutrients 2018; 10 (07) 855
• 175 Mosquera Marta EG, Jiménez G, Tabernero V. et al. Terpenes and terpenoids: building blocks to produce biopolymers. Sustain Chem 2021; 2 (03) 467-492
• 176 Ninkuu V, Zhang L, Yan J, Fu Z, Yang T, Zeng H. Biochemistry of terpenes and recent advances in plant protection. Int J Mol Sci 2021; 22 (11) 5710
• 177 Zhou Y, Wang J, Zhang D. et al. Mechanism of drug-induced liver injury and hepatoprotective effects of natural drugs. Chin Med 2021; 16 (01) 135
• 178 Baccouri B, Rajhi I. Potential antioxidant activity of terpenes. In: Perveen S, Mohammad Al-Taweel A. eds. Biochemistry. Vol 21. IntechOpen; 2021.
• 179 El-Emam SZ, Soubh AA, Al-Mokaddem AK, Abo El-Ella DM. Geraniol activates Nrf-2/HO-1 signaling pathway mediating protection against oxidative stress-induced apoptosis in hepatic ischemia-reperfusion injury. Naunyn Schmiedebergs Arch Pharmacol 2020; 393 (10) 1849-1858
• 180 Vinholes J, Rudnitskaya A, Gonçalves P, Martel F, Coimbra MA, Rocha SM. Hepatoprotection of sesquiterpenoids: a quantitative structure-activity relationship (QSAR) approach. Food Chem 2014; 146: 78-84
• 181 Bai Y, Peng W, Yang C. et al. Pharmacokinetics and metabolism of naringin and active metabolite naringenin in rats, dogs, humans, and the differences between species. Front Pharmacol 2020; 11: 364
• 182 Chen C, Yin Q, Tian J. et al. Studies on the changes of pharmacokinetics behaviors of phytochemicals and the influence on endogenous metabolites after the combination of Radix Bupleuri and Radix Paeoniae Alba based on multi-component pharmacokinetics and metabolomics. Front Pharmacol 2021; 12: 630970
• 183 Mansour DF, Abdallah HMI, Ibrahim BMM, Hegazy RR, Esmail RSE, Abdel-Salam LO. The carcinogenic agent diethylnitrosamine induces early oxidative stress, inflammation and proliferation in rat liver, stomach and colon: protective effect of ginger extract. Asian Pac J Cancer Prev 2019; 20 (08) 2551-2561
• 184 Khan SU, Lone AN, Khan MS. et al. Effect of omega-3 fatty acids on cardiovascular outcomes: a systematic review and meta-analysis. EClinicalMedicine 2021; 38: 100997
• 185 Srimal RC, Dhawan BN. Pharmacology of diferuloyl methane (curcumin), a non-steroidal anti-inflammatory agent. J Pharm Pharmacol 1973; 25 (06) 447-452
• 186 Agarwal KA, Tripathi CD, Agarwal BB, Saluja S. Efficacy of turmeric (curcumin) in pain and postoperative fatigue after laparoscopic cholecystectomy: a double-blind, randomized placebo-controlled study. Surg Endosc 2011; 25 (12) 3805-3810
• 187 Amalraj A, Varma K, Jacob J. et al. A novel highly bioavailable curcumin formulation improves symptoms and diagnostic indicators in rheumatoid arthritis patients: a randomized, double-blind, placebo-controlled, two-dose, three-arm, and parallel-group study. J Med Food 2017; 20 (10) 1022-1030
• 188 Hanai H, Iida T, Takeuchi K. et al. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2006; 4 (12) 1502-1506
• 189 Méndez-del Villar M, González-Ortiz M, Martínez-Abundis E, Pérez-Rubio KG, Lizárraga-Valdez R. Effect of resveratrol administration on metabolic syndrome, insulin sensitivity, and insulin secretion. Metab Syndr Relat Disord 2014; 12 (10) 497-501
• 190 Korsholm AS, Kjær TN, Ornstrup MJ, Pedersen SB. Comprehensive metabolomic analysis in blood, urine, fat, and muscle in men with metabolic syndrome: a randomized, placebo-controlled clinical trial on the effects of resveratrol after four months' treatment. Int J Mol Sci 2017; 18 (03) 554
• 191 Liu H, Ye M, Guo H. An updated review of randomized clinical trials testing the improvement of cognitive function of Ginkgo biloba extract in healthy people and Alzheimer's patients. Front Pharmacol 2020; 10: 1688
• 192 Pagotto GLO, Santos LMOD, Osman N. et al. Ginkgo biloba: a leaf of hope in the fight against Alzheimer's dementia: clinical trial systematic review. Antioxidants 2024; 13 (06) 651
• 193 Bril F, Biernacki DM, Kalavalapalli S. et al. Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 2019; 42 (08) 1481-1488
• 194 Schrieber SJ, Hawke RL, Wen Z. et al. Differences in the disposition of Silymarin between patients with nonalcoholic fatty liver disease and chronic hepatitis C. Drug Metab Dispos 2011; 39 (12) 2182-2190
• 195 Milosevic N, Milanovic M, Abenavoli L, Milic N. Phytotherapy and NAFLD - from Goals and Challenges to Clinical Practice. Accessed August 8, 2024 at: https://www.eurekaselect.com/article/64010
• 196 Hang W, Shu H, Wen Z. et al. N-acetyl cysteine ameliorates high-fat diet-induced nonalcoholic fatty liver disease and intracellular triglyceride accumulation by preserving mitochondrial function. Front Pharmacol 2021; 12: 636204
• 197 Gulati K, Ray A, Vijayan VK. Assessment of protective role of polyherbal preparation, Livina, against anti-tubercular drug induced liver dysfunction. IJEB Vol4803 March 2010 . Published online March 2010. Accessed August 8, 2024 at: http://nopr.niscpr.res.in/handle/123456789/7409
• 198 Wang Y, Wang Z, Gao M. et al. Efficacy and safety of magnesium isoglycyrrhizinate injection in patients with acute drug-induced liver injury: a phase II trial. Liver Int 2019; 39 (11) 2102-2111
• 199 Abstracts of the 26th Annual Conference of APASL,. February 15–19, 2017, Shanghai, China. Hepatol Int 2017; 11 (01) 839-840
• 200 Vincenzi B, Santini D, Frezza AM. et al. The role of S-adenosyl methionine in preventing FOLFOX-induced liver toxicity: a retrospective analysis in patients affected by resected colorectal cancer treated with adjuvant FOLFOX regimen. Expert Opin Drug Saf 2011; 10 (03) 345-349
• 201 Adebowale AO, Liang Z, Eddington ND. Nutraceuticals, a call for quality control of delivery systems: a case study with chondroitin sulfate and glucosamine. J Nutraceuticals Funct Med Foods 2000; 2 (02) 15-30
• 202 Mazzanti G, Menniti-Ippolito F, Moro PA. et al. Hepatotoxicity from green tea: a review of the literature and two unpublished cases. Eur J Clin Pharmacol 2009; 65 (04) 331-341
• 203 Lambert JD, Kennett MJ, Sang S, Reuhl KR, Ju J, Yang CS. Hepatotoxicity of high oral dose (-)-epigallocatechin-3-gallate in mice. Food Chem Toxicol 2010; 48 (01) 409-416
• 204 Di Francia R, Berretta M, Benincasa G. et al. Pharmacogenetic-based interactions between nutraceuticals and angiogenesis inhibitors. Cells 2019; 8 (06) 522
• 205 Dwyer JT, Coates PM, Smith MJ. Dietary supplements: regulatory challenges and research resources. Nutrients 2018; 10 (01) 41
• 206 Dima C, Assadpour E, Dima S, Jafari SM. Bioavailability of nutraceuticals: Role of the food matrix, processing conditions, the gastrointestinal tract, and nanodelivery systems. Compr Rev Food Sci Food Saf 2020; 19 (03) 954-994 . Doi: 1
• 207 Suzuki S, Muroishi Y, Nakanishi I, Oda Y. Relationship between genetic polymorphisms of drug-metabolizing enzymes (CYP1A1, CYP2E1, GSTM1, and NAT2), drinking habits, histological subtypes, and p53 gene point mutations in Japanese patients with gastric cancer. J Gastroenterol 2004; 39 (03) 220-230
• 208 Jamshed N, Raza I, Rasheed A, Jamshed N, Akhtar L, Rashid N. Impact of aqueous neem leave extract on erythromycin induced hepatotoxicity. Pak Armed Forces Med J 2022; 72 (01) 235-239
• 209 Gupta A, Kumar R, Ganguly R, Singh AK, Rana HK, Pandey AK. Antioxidant, anti-inflammatory and hepatoprotective activities of Terminalia bellirica and its bioactive component ellagic acid against diclofenac induced oxidative stress and hepatotoxicity. Toxicol Rep 2020; 8: 44-52
• 210 Akindele AJ, Oludadepo GO, Amagon KI, Singh D, Osiagwu DD. Protective effect of carvedilol alone and coadministered with diltiazem and prednisolone on doxorubicin and 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats. Pharmacol Res Perspect 2018; 6 (01) e00381
• 211 Lei S, Gu R, Ma X. Clinical perspectives of isoniazid-induced liver injury. Liver Res 2021; 5 (02) 45-52
• 212 Ahmad MH, Fatima M, Hossain M, Mondal AC. Evaluation of naproxen-induced oxidative stress, hepatotoxicity and in-vivo genotoxicity in male Wistar rats. J Pharm Anal 2018; 8 (06) 400-406
• 213 Patocka J, Wu Q, Nepovimova E, Kuca K. Phenytoin - an anti-seizure drug: overview of its chemistry, pharmacology and toxicology. Food Chem Toxicol 2020; 142: 111393
• 214 Bhardwaj M, Bhardwaj NJ, Cueto K, Killeen TC. Hydralazine-induced liver injury: a review and discussion. BMJ Case Rep 2021; 14 (08) e243278
• 215 Castelo-Branco C, Del Pino M. Hepatotoxicity during low-dose flutamide treatment for hirsutism. Gynecol Endocrinol 2009; 25 (07) 419-422
• 216 Leong RW, Gearry RB, Sparrow MP. Thiopurine hepatotoxicity in inflammatory bowel disease: the role for adding allopurinol. Expert Opin Drug Saf 2008; 7 (05) 607-616
• 217 Waterbury LD, Silliman D, Jolas T. Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium. Curr Med Res Opin 2006; 22 (06) 1133-1140
• 218 Luk T, Edwards BD, Bates D, Evernden C, Edwards J. Nitrofurantoin-induced liver failure: a fatal yet forgotten complication. Can Fam Physician 2021; 67 (05) 342-344
• 219 Rousta AM, Mirahmadi SMS, Shahmohammadi A. et al. Therapeutic potential of isorhamnetin following acetaminophen-induced hepatotoxicity through targeting NLRP3/NF-κB/Nrf2. Drug Res (Stuttg) 2022; 72 (05) 245-254
• 220 Satvati M, Salehi-Vanani N, Nouri A, Heidarian E. Protective effects of N-acetyl cysteine against oxidative stress in ibuprofen-induced hepatotoxicity in rats. Comp Clin Pathol 2022; 31 (02) 293-301
• 221 Altay D, Pamukçu Ö, Baykan A, Üzüm K, Arslan D. Aspirin-induced hepatotoxicity and anemia in children with acute rheumatic fever. Turk J Pediatr 2021; 63 (02) 193-199
• 222 Ekere OU, Monago-Ighorodje CC, Ogunka-Nnoka CU. Nutrient, bioactive components and effects of ethanol extracts of annona muricata leaves and fagara zanthoxyloide roots on zidovudine-induced oxidative stress in Wistar Rats. J Appl Life Sci Int 2019;
• 223 Iqbal MO, Manzoor M, Mumtaz A. et al. Evaluation of the hepatoprotective activity of hydroalcoholic extract of Alhagi camelorum against valproic acid-induced hepatotoxicity in rats. Biomed Pharmacother 2022; 150: 112953
• 224 Popp T, Balszuweit F, Schmidt A, Eyer F, Thiermann H, Steinritz D. Assessment of α-amanitin toxicity and effects of silibinin and penicillin in different in vitro models. Toxicol In Vitro 2020; 67: 104921
• 225 Zou W, Devi SS, Sparkenbaugh E, Younis HS, Roth RA, Ganey PE. Hepatotoxic interaction of sulindac with lipopolysaccharide: role of the hemostatic system. Toxicol Sci 2009; 108 (01) 184-193
• 226 Bai Z, Jia K, Chen G. et al. Carbamazepine induces hepatotoxicity in zebrafish by inhibition of the Wnt/β-catenin signaling pathway. Environ Pollut 2021; 276: 116688
• 227 Hassan AS, Ahmed JH, Al-Haroon SS. A study of the effect of Nigella sativa (Black seeds) in isoniazid (INH)-induced hepatotoxicity in rabbits. Indian J Pharmacol 2012; 44 (06) 678-682
• 228 Slim R, Ben Salem C, Hmouda H, Bouraoui K. Hepatotoxicity of alpha-methyldopa in pregnancy. J Clin Pharm Ther 2010; 35 (03) 361-363
• 229 Thompson M, Jaiswal Y, Wang I, Williams L. Hepatotoxicity: treatment, causes and applications of medicinal plants as therapeutic agents. J Phytopharm 2017; 6 (03) 186-193
• 230 Wang X, Liu J, Zhang X. et al. Seabuckthorn berry polysaccharide extracts protect against acetaminophen induced hepatotoxicity in mice via activating the Nrf-2/HO-1-SOD-2 signaling pathway. Phytomedicine 2018; 38: 90-97
• 231 Yang LL, Xiao N, Li XW. et al. Pharmacokinetic comparison between quercetin and quercetin 3-O-β-glucuronide in rats by UHPLC-MS/MS. Sci Rep 2016; 6 (01) 35460
• 232 Abdel-Rahman RF, Fayed HM, Ogaly HA, Hussein RA, Raslan MA. Phytoconstituents of Sansevieria suffruticosa N.E.Br. Leaves and its hepatoprotective effect via activation of the NRF2/ARE signaling pathway in an experimentally induced liver fibrosis rat model. Chem Biodivers 2022; 19 (04) e202100960
• 233 Shahrzad S, Aoyagi K, Winter A, Koyama A, Bitsch I. Pharmacokinetics of gallic acid and its relative bioavailability from tea in healthy humans. J Nutr 2001; 131 (04) 1207-1210
• 234 Wei X, Luo C, He Y. et al. Hepatoprotective effects of different extracts from Triphala against CCl₄-induced acute liver injury in mice. Front Pharmacol 2021; 12: 664607
• 235 Antunes-Ricardo M, Rodríguez-Rodríguez C, Gutiérrez-Uribe JA, Cepeda-Cañedo E, Serna-Saldívar SO. Bioaccessibility, intestinal permeability and plasma stability of isorhamnetin glycosides from Opuntia ficus-indica (L.). Int J Mol Sci 2017; 18 (08) 1816
• 236 Feng XH, Xu HY, Wang JY, Duan S, Wang YC, Ma CM. In vivo hepatoprotective activity and the underlying mechanism of chebulinic acid from Terminalia chebula fruit. Phytomedicine 2021; 83: 153479
• 237 Ou-yang Z, Cao X, Wei Y, Zhang WWQ, Zhao M. Duan J-ao. Pharmacokinetic study of rutin and quercetin in rats after oral administration of total flavones of mulberry leaf extract. Rev Bras Farmacogn 2013; 23 (05) 776-782
• 238 Ma JQ, Ding J, Zhang L, Liu CM. Protective effects of ursolic acid in an experimental model of liver fibrosis through Nrf2/ARE pathway. Clin Res Hepatol Gastroenterol 2015; 39 (02) 188-197
• 239 Janle EM, Morré DM, Morré DJ, Zhou Q, Zhu Y. Pharmacokinetics of green tea catechins in extract and sustained-release preparations. J Diet Suppl 2008; 5 (03) 248-263
• 240 Motawi TK, Ahmed SA, El-Boghdady NA, Metwally NS, Nasr NN. Impact of betanin against paracetamol and diclofenac induced hepato-renal damage in rats. Biomarkers 2020; 25 (01) 86-93
• 241 Manupuri P, Indala R, Jagaralmudi A, Kumar R. Hepatoprotective effect of inularacemosa on hepatic ischemia/reperfusion induced injury in rats. J Bioanal Biomed 2013; 05 (02)
• 242 Lin X, Bai D, Wei Z. et al. Curcumin attenuates oxidative stress in RAW264.7 cells by increasing the activity of antioxidant enzymes and activating the Nrf2-Keap1 pathway. PLoS One 2019; 14 (05) e0216711
• 243 Shin DH, Cho HJ, Park SH. et al. HPLC analysis of ferulic acid and its pharmacokinetics after intravenous bolus administration in rats. J Biomed Transl Res 2016; 17 (01) 1-7
• 244 Lv Z, Wu W, Ge S. et al. Naringin protects against perfluorooctane sulfonate-induced liver injury by modulating NRF2 and NF-κB in mice. Int Immunopharmacol 2018; 65: 140-147
• 245 Chu KO, Pang CCP. Pharmacokinetics and disposition of green tea catechins. In: Malangu N. ed. Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors. InTech 2018.
• 246 Jia R, Gu Z, He Q. et al. Anti-oxidative, anti-inflammatory and hepatoprotective effects of Radix Bupleuri extract against oxidative damage in tilapia (Oreochromis niloticus) via Nrf2 and TLRs signaling pathway. Fish Shellfish Immunol 2019; 93: 395-405
• 247 Legette L, Ma L, Reed RL. et al. Pharmacokinetics of xanthohumol and metabolites in rats after oral and intravenous administration. Mol Nutr Food Res 2012; 56 (03) 466-474
• 248 Lu Q, Tan S, Gu W. et al. Phytochemical composition, isolation and hepatoprotective activity of active fraction from Veronica ciliata against acetaminophen-induced acute liver injury via p62-Keap1-Nrf2 signaling pathway. J Ethnopharmacol 2019; 243: 112089
• 249 Lei F, Xing DM, Xiang L. et al. Pharmacokinetic study of ellagic acid in rat after oral administration of pomegranate leaf extract. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 796 (01) 189-194
• 250 Lu Q, Gu W, Luo C. et al. Phytochemical characterization and hepatoprotective effect of active fragment from Adhatoda vasica Nees. against tert-butyl hydroperoxide induced oxidative impairment via activating AMPK/p62/Nrf2 pathway. J Ethnopharmacol 2021; 266: 113454
• 251 Kanwal HA, Majeed W, Awan AM, Aslam B. Polyphenols from green tea revert CCl4-induced liver oxidative stress and inflammation associated with high fat diet by activation of NRF-2 and TIMP-1 pathways to neutralize ROS. 2022;
• 252 Zhou RJ, Ye H, Wang F, Wang JL, Xie ML. Apigenin inhibits d-galactosamine/LPS-induced liver injury through upregulation of hepatic Nrf-2 and PPARγ expressions in mice. Biochem Biophys Res Commun 2017; 493 (01) 625-630
• 253 Liu XW, Yang JL, Niu W. et al. Human pharmacokinetics of ginkgo terpene lactones and impact of carboxylation in blood on their platelet-activating factor antagonistic activity. Acta Pharmacol Sin 2018; 39 (12) 1935-1946
• 254 Gutierres VO, Campos ML, Arcaro CA. et al. Curcumin pharmacokinetic and pharmacodynamic evidences in streptozotocin-diabetic rats support the antidiabetic activity to be via metabolite(s). Evid Based Complement Alternat Med 2015; 2015: 678218
• 255 Lin G, Luo D, Liu J. et al. Hepatoprotective effect of polysaccharides isolated from Dendrobium officinale against acetaminophen-induced liver injury in mice via regulation of the Nrf2-Keap1 signaling pathway. Oxid Med Cell Longev 2018; 2018: 6962439
• 256 Pavan B, Dalpiaz A, Marani L. et al. Geraniol pharmacokinetics, bioavailability and its multiple effects on the liver antioxidant and xenobiotic-metabolizing enzymes. Front Pharmacol 2018; 9: 18
• 257 Kim DY, Choi BY. Costunolide - a bioactive sesquiterpene lactone with diverse therapeutic potential. Int J Mol Sci 2019; 20 (12) 2926
• 258 Wang Z, Geng L, Chen Z, Lin B, Zhang M, Zheng S. In vivo therapeutic potential of Inula racemosa in hepatic ischemia-reperfusion injury following orthotopic liver transplantation in male albino rats. AMB Express 2017; 7 (01) 211
• 259 Huang W, Wang Y, Jiang X, Sun Y, Zhao Z, Li S. Protective effect of flavonoids from ziziphus jujuba cv. jinsixiaozao against acetaminophen-induced liver injury by inhibiting oxidative stress and inflammation in mice. Molecules 2017; 22 (10) 1781
• 260 Madadi E, Mazloum-Ravasan S, Yu JS, Ha JW, Hamishehkar H, Kim KH. Therapeutic application of Betalains: a review. Plants 2020; 9 (09) 1219
• 261 Singh S, Singh DK, Meena A, Dubey V, Masood N, Luqman S. Rutin protects t–butyl hydroperoxide-induced oxidative impairment via modulating the Nrf2 and iNOS activity. Phytomedicine 2019; 55: 92-104
• 262 Yang SY, Pyo MC, Nam MH, Lee KW. ERK/Nrf2 pathway activation by caffeic acid in HepG2 cells alleviates its hepatocellular damage caused by t-butylhydroperoxide-induced oxidative stress. BMC Complement Altern Med 2019; 19 (01) 139
• 263 Krajka-Kuźniak V, Paluszczak J, Baer-Dubowska W. Xanthohumol induces phase II enzymes via Nrf2 in human hepatocytes in vitro. Toxicol In Vitro 2013; 27 (01) 149-156
• 264 Miao L, Yang Y, Li Z, Fang Z, Zhang Y, Han CC. Ginsenoside Rb2: a review of pharmacokinetics and pharmacological effects. J Ginseng Res 2022; 46 (02) 206-213
• 265 Zhang PW, Chen FX, Li D, Ling WH, Guo HHA. A CONSORT-compliant, randomized, double-blind, placebo-controlled pilot trial of purified anthocyanin in patients with nonalcoholic fatty liver disease. Medicine (Baltimore) 2015; 94 (20) e758
• 266 Nambiar A, Kellogg III D, Justice J. et al. Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine 2023; 90: 104481
• 267 Ferk F, Kundi M, Brath H. et al. Gallic acid improves health-associated biochemical parameters and prevents oxidative damage of DNA in type 2 diabetes patients: results of a placebo-controlled pilot study. Mol Nutr Food Res 2018; 62 (04) 1700482
• 268 Egert S, Bosy-Westphal A, Seiberl J. et al. Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br J Nutr 2009; 102 (07) 1065-1074
• 269 Sakata R, Nakamura T, Torimura T, Ueno T, Sata M. Green tea with high-density catechins improves liver function and fat infiltration in non-alcoholic fatty liver disease (NAFLD) patients: a double-blind placebo-controlled study. Int J Mol Med 2013; 32 (05) 989-994
• 270 Acosta L, Byham-Gray L, Kurzer M, Samavat H. Hepatotoxicity with high-dose green tea extract: effect of catechol-O-methyltransferase and uridine 5′-diphospho-glucuronosyltransferase 1A4 genotypes. J Diet Suppl 2023; 20 (06) 850-869
• 271 Kumar NB, Pow-Sang J, Spiess PE. et al. Randomized, placebo-controlled trial evaluating the safety of one-year administration of green tea catechins. Oncotarget 2016; 7 (43) 70794-70802
• 272 Aziz TA, Hussain SA, Mahwi TO, Ahmed ZA, Rahman HS, Rasedee A. The efficacy and safety of Ginkgo biloba extract as an adjuvant in type 2 diabetes mellitus patients ineffectively managed with metformin: a double-blind, randomized, placebo-controlled trial. Drug Des Devel Ther 2018; 12: 735-742
• 273 Huang Z, Wei W, Zhong Q. Effect of sodium ferulate on hemodynamics in hepatic cirrhosis patients with portal hypertension. [article in Chinese]. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 2008; 28 (07) 640-642
• 274 Ramírez-Rodríguez AM, González-Ortiz M, Martínez-Abundis E, Acuña Ortega N. Effect of ursolic acid on metabolic syndrome, insulin sensitivity, and inflammation. J Med Food 2017; 20 (09) 882-886
• 275 Asghari E, Rashidlamir A, Hosseini SRA, Moazzami M, Samarghandian S, Farkhondeh T. Synergism effects of ursolic acid supplementation on the levels of irisin, C-reactive protein, IL-6, and TNF-α during high-intensity resistance training in low activity men. Cardiovasc Hematol Disord Drug Targets 2020; 20 (02) 138-144
• 276 Church DD, Schwarz NA, Spillane MB. et al. L-Leucine increases skeletal muscle IGF-1 but does not differentially increase Akt/mTORC1 signaling and serum IGF-1 compared to ursolic acid in response to resistance exercise in resistance-trained men. J Am Coll Nutr 2016; 35 (07) 627-638
• 277 Mielgo-Ayuso J, Barrenechea L, Alcorta P, Larrarte E, Margareto J, Labayen I. Effects of dietary supplementation with epigallocatechin-3-gallate on weight loss, energy homeostasis, cardiometabolic risk factors and liver function in obese women: randomised, double-blind, placebo-controlled clinical trial. Br J Nutr 2014; 111 (07) 1263-1271
• 278 Siblini H, Al-Hendy A, Segars J. et al. Assessing the hepatic safety of epigallocatechin gallate (EGCG) in reproductive-aged women. Nutrients 2023; 15 (02) 320
• 279 Dabrowski W, Gagos M, Siwicka-Gieroba D. et al. Humulus lupus extract rich in xanthohumol improves the clinical course in critically ill COVID-19 patients. Biomed Pharmacother 2023; 158: 114082
• 280 Langley BO, Ryan JJ, Hanes D. et al. Xanthohumol microbiome and signature in healthy adults (the XMaS trial): safety and tolerability results of a phase I triple-masked, placebo-controlled clinical trial. Mol Nutr Food Res 2021; 65 (08) e2001170
• 281 Hajiluian G, Karegar SJ, Shidfar F. et al. The effects of ellagic acid supplementation on neurotrophic, inflammation, and oxidative stress factors, and indoleamine 2, 3-dioxygenase gene expression in multiple sclerosis patients with mild to moderate depressive symptoms: a randomized, triple-blind, placebo-controlled trial. Phytomedicine 2023; 121: 155094
• 282 Department of Nutrition, School of Health, Qazvin University of Medical Sciences, Qazvin, Iran;. Mirzaie Z, Bastani A. et al. Improving effect of ellagic acid on sleep quality and gastrointestinal symptoms in patient with irritable bowel syndrome: randomized double-blind clinical trial. Turk J Gastroenterol 2021; 32 (11) 937-944
• 283 Ghadimi M, Foroughi F, Hashemipour S. et al. Randomized double-blind clinical trial examining the ellagic acid effects on glycemic status, insulin resistance, antioxidant, and inflammatory factors in patients with type 2 diabetes. Phytother Res 2021; 35 (02) 1023-1032
• 284 Ferro Y, Maurotti S, Mazza E. et al. Citrus bergamia and cynara cardunculus reduce serum uric acid in individuals with non-alcoholic fatty liver disease. Medicina (Kaunas) 2022; 58 (12) 1728
• 285 Lirussi F, Beccarello A, Zanette G. et al. Silybin-beta-cyclodextrin in the treatment of patients with diabetes mellitus and alcoholic liver disease. Efficacy study of a new preparation of an anti-oxidant agent. Diabetes Nutr Metab 2002; 15 (04) 222-231
• 286 Yari Z, Movahedian M, Imani H, Alavian SM, Hedayati M, Hekmatdoost A. The effect of hesperidin supplementation on metabolic profiles in patients with metabolic syndrome: a randomized, double-blind, placebo-controlled clinical trial. Eur J Nutr 2020; 59 (06) 2569-2577
• 287 Saadati S, Sadeghi A, Mansour A. et al. Curcumin and inflammation in non-alcoholic fatty liver disease: a randomized, placebo controlled clinical trial. BMC Gastroenterol 2019; 19 (01) 133
• 288 Mirhafez SR, Dehabeh M, Hariri M. et al. Curcumin and piperine combination for the treatment of patients with non-alcoholic fatty liver disease: a double-blind randomized placebo-controlled trial. In: Sahebkar A, Sathyapalan T. eds. Natural Products and Human Diseases. Vol 1328. Advances in Experimental Medicine and Biology. Springer International Publishing; 2021: 11-19
• 289 Ricci C, Rizzello F, Valerii MC. et al. Geraniol treatment for irritable bowel syndrome: a double-blind randomized clinical trial. Nutrients 2022; 14 (19) 4208
• 290 Namkhah Z, Naeini F, Mahdi Rezayat S, Mehdi Yaseri, Mansouri S, Javad Hosseinzadeh-Attar M. Does naringenin supplementation improve lipid profile, severity of hepatic steatosis and probability of liver fibrosis in overweight/obese patients with NAFLD? A randomised, double-blind, placebo-controlled, clinical trial. Int J Clin Pract 2021; 75 (11) e14852
• 291 Van den Eynde MDG, Geleijnse JM, Scheijen JLJM. et al. Quercetin, but not epicatechin, decreases plasma concentrations of methylglyoxal in adults in a randomized, double-blind, placebo-controlled, crossover trial with pure flavonoids. J Nutr 2018; 148 (12) 1911-1916
• 292 Zhou B, Yan Z, Liu R. et al. Prospective study of transcatheter arterial chemoembolization (TACE) with Ginsenoside Rg3 versus TACE alone for the treatment of patients with advanced hepatocellular carcinoma. Radiology 2016; 280 (02) 630-639
• 293 Feng YL, Ling CQ, Chen Z, Li B, Gu W. Ginsenosides and dexamethasone in managing the liver injury and renal function after transcatheter arterial chemoembolization for hepatic carcinoma patient. [article in Chinese]. Zhonghua Zhong Liu Za Zhi 2006; 28 (11) 844-847