An Insight into Different Experimental Models used for Hepatoprotective
Studies: A Review

Sucharita      Babu; Santosh   K   Ranajit; Gurudutta      Pattnaik; Goutam      Ghosh; Goutam      Rath; Biswakanth      Kar
doi:10.2174/0115701638278844231214115102
Abstract

Numerous factors, including exposure to harmful substances, drinking too much alcohol, contracting certain hepatitis serotypes, and using specific medicines, contribute to the development of liver illnesses. Lipid peroxidation and other forms of oxidative stress are the main mechanisms by which hepatotoxic substances harm liver cells. Pathological changes in the liver include a rise in the levels of blood serum, a decrease in antioxidant enzymes, as well as the formation of free radical radicals. It is necessary to find pharmaceutical alternatives to treat liver diseases to increase their efficacy and decrease their toxicity. For the development of new therapeutic medications, a greater knowledge of primary mechanisms is required. In order to mimic human liver diseases, animal models are developed. Animal models have been used for several decades to study the pathogenesis of liver disorders and related toxicities. For many years, animal models have been utilized to investigate the pathophysiology of liver illness and associated toxicity. The animal models are created to imitate human hepatic disorders. This review enlisted numerous hepatic damage in vitro and in vivo models using various toxicants, their probable biochemical pathways and numerous metabolic pathways via oxidative stressors, different serum biomarkers enzymes are discussed, which will help to identify the most accurate and suitable model to test any plant preparations to check and evaluate their hepatoprotective properties.
Graphical Abstract

[1]
Ahmad G, Masoodi MH, Tabassum N, Mir SA, Iqbal MJ. In vivo hepatoprotective potential of extracts obtained from floral spikes of Prunella vulgaris L. J Ayurveda Integr Med  2020; 11(4): 502-7.
 [http://dx.doi.org/10.1016/j.jaim.2019.08.003] [PMID:  32241633]

[2]
Neuman MG. Hepatotoxicity: Mechanisms of liver injury. Liver Diseases: A Multidisciplinary Textbook  2020; 75-84.
 [http://dx.doi.org/10.1007/978-3-030-24432-3_7]

[3]
Bogdanos DP, Gao B, Gershwin ME. Liver immunology. Compr Physiol  2013; 3(2): 567-98.
 [http://dx.doi.org/10.1002/cphy.c120011] [PMID:  23720323]

[4]
Bigoniya P, Singh CS, Shukla A. A comprehensive review of different liver toxicants used in experimental pharmacology. Int J Pharm Sci Drug Res  2009; 1(3): 124-35.

[5]
Adwas AA, Elsayed A, Azab AE, Quwaydir FA. Oxidative stress and antioxidant mechanisms in human body. J Appl Biotechnol Bioeng  2019; 6(1): 43-7.

[6]
Iqubal A, Iqubal MK, Haque SE. Experimental hepatotoxicity inducing agents: A Review. Int J Clin Pharmacol Res  2016; 6(11): 325-5.

[7]
Gyssens IC. Animal models for research in human infectious diseases. CMI editorial policy. Clin Microbiol Infect  2019; 25(6): 649-50.
 [http://dx.doi.org/10.1016/j.cmi.2019.04.010] [PMID:  30986559]

[8]
Ahmad F, Tabassum N. Experimental models used for the study of antihepatotoxic agents. J Acute Dis  2012; 1(2): 85-9.
 [http://dx.doi.org/10.1016/S2221-6189(13)60021-9]

[9]
Kumar A, Susmitha K, Swathy B, Ramu E, Venkatesh B. A review on liver disorders and screening models of hepatoprotective agents. Int J Allied Med Sci Clin Res  2014; 2: 136-50.

[10]
Bhakuni GS, Bedi O, Bariwal J, Deshmukh R, Kumar P. Animal models of hepatotoxicity. Inflamm Res  2016; 65(1): 13-24.
 [http://dx.doi.org/10.1007/s00011-015-0883-0] [PMID:  26427493]

[11]
Kashaw V, Nema AK, Agarwal A. Hepatoprotective prospective of herbal drugs and their vesicular carriers–a review. Int J Res Pharm Biomed Sci  2011; 2(2): 360-74.

[12]
Patil BR, Bamane SH, Khadsare UR. In vitro protection of hepatocytes by Alocasia macrorrhiza leaf juice against CCL4 and Tylenol mediated hepatic injury. Int J Pharm Appl  2011; 2(2): 122-7.

[13]
Vodovotz Y, Kim P, Bagci E, et al. Inflammatory modulation of hepatocyte apoptosis by nitric oxide: In vivo, in vitro, and in silico studies. Curr Mol Med  2004; 4(7): 753-62.
 [http://dx.doi.org/10.2174/1566524043359944] [PMID:  15579022]

[14]
Olinga P, Schuppan D. Precision-cut liver slices: A tool to model the liver ex vivo. J Hepatol  2013; 58(6): 1252-3.
 [http://dx.doi.org/10.1016/j.jhep.2013.01.009] [PMID:  23336979]

[15]
Bala A, Haldar PK, Kar B, Naskar S, Mazumder UK. Carbon tetrachloride: A hepatotoxin causes oxidative stress in murine peritoneal macrophage and peripheral blood lymphocyte cells. Immunopharmacol Immunotoxicol  2012; 34(1): 157-62.
 [http://dx.doi.org/10.3109/08923973.2011.590498] [PMID:  21721906]

[16]
Al Amin ASM, Menezes RG. Carbon tetrachloride toxicity. In: StatPearls Treasure Island. FL: StatPearls Publishing 2023. Updated 2023 Jul 16 Internet 

[17]
Kar B, Ghosh G, Rath G, Bhattacharya S. Hepatoprotective activity and antioxidant role of hymen-odictyon excelsum bark against paracetamol-induced hepatotoxicity in rats. Curr Trends Biotechnol Pharm  2022; 16(2): 203-10.

[18]
Liu Y, Meyer C, Xu C, et al. Animal models of chronic liver diseases. Am J Physiol Gastrointest Liver Physiol  2013; 304(5): G449-68.
 [http://dx.doi.org/10.1152/ajpgi.00199.2012] [PMID:  23275613]

[19]
Thrall KD, Vucelick ME, Gies RA, et al. Comparative metabolism of carbon tetrachloride in rats, mice, and hamsters using gas uptake and PBPK modeling. J Toxicol Environ Health A  2000; 60(8): 531-48.
 [http://dx.doi.org/10.1080/00984100050082085] [PMID:  10983521]

[20]
Nazir N, Muhammad J, Ghaffar R, et al. Phytochemical profiling and antioxidant potential of Daphne mucronata Royle and action against paracetamol-induced hepatotoxicity and nephrotoxicity in rabbits. Saudi J Biol Sci  2021; 28(9): 5290-301.
 [http://dx.doi.org/10.1016/j.sjbs.2021.05.051] [PMID:  34466107]

[21]
Zakaria ZA, Kamisan FH, Kek TL, Salleh MZ. Hepatoprotective and antioxidant activities of Dicranopteris linearis leaf extract against paracetamol-induced liver intoxication in rats. Pharm Biol  2020; 58(1): 478-89.
 [http://dx.doi.org/10.1080/13880209.2020.1764058] [PMID:  32476526]

[22]
Gebremedhin G, Tuem KB, Kahsu A, Balasubramanian R. In vitro antioxidant and in vivo hepatoprotective activities of root bark extract and solvent fractions of Croton macrostachyus hochst. Ex del.(Euphorbiaceae) on paracetamol-induced liver damage in mice. J Exp Pharmacol  2020; 12: 301-11.
 [http://dx.doi.org/10.2147/JEP.S259081] [PMID:  32982486]

[23]
Tolba R, Kraus T, Liedtke C, Schwarz M, Weiskirchen R. Diethylnitrosamine (DEN)-induced carcinogenic liver injury in mice. Lab Anim  2015; 49(1_suppl)(Suppl.): 59-69.
 [http://dx.doi.org/10.1177/0023677215570086] [PMID:  25835739]

[24]
Li Y, Hecht SS. Metabolic activation and DNA interactions of carcinogenic N-nitrosamines to which humans are commonly exposed. Int J Mol Sci  2022; 23(9): 4559.
 [http://dx.doi.org/10.3390/ijms23094559] [PMID:  35562949]

[25]
Schulien I, Hasselblatt P. Diethylnitrosamine-induced liver tumorigenesis in mice. Methods Cell Biol  2021; 163: 137-52.
 [http://dx.doi.org/10.1016/bs.mcb.2020.08.006] [PMID:  33785162]

[26]
Park DH, Shin JW, Park SK, et al. Diethylnitrosamine (DEN) induces irreversible hepatocellular carcinogenesis through overexpression of G1/S-phase regulatory proteins in rat. Toxicol Lett  2009; 191(2-3): 321-6.
 [http://dx.doi.org/10.1016/j.toxlet.2009.09.016] [PMID:  19822196]

[27]
Santos NP, Colaço AA, Oliveira PA. Animal models as a tool in hepatocellular carcinoma research: A Review. Tumour Biol  2017; 39(3)
 [http://dx.doi.org/10.1177/1010428317695923] [PMID:  28347231]

[28]
Schmähl D, Preussmann R, Hamperl H. Leberkrebs-erzeugende Wirkung von Diäthylnitrosamin nach oraler Gabe bei Ratten. Naturwissenschaften  1960; 47(4): 89.
 [http://dx.doi.org/10.1007/BF00628490]

[29]
Yang CS, Tu YY, Koop DR, Coon MJ. Metabolism of nitrosamines by purified rabbit liver cytochrome P-450 isozymes. Cancer Res  1985; 45(3): 1140-5.
 [PMID:  3971365]

[30]
Saber S, Ghanim AMH, El-Ahwany E, El-Kader EMA. Novel complementary antitumour effects of celastrol and metformin by targeting IκBκB, apoptosis and NLRP3 inflammasome activation in diethylnitrosamine-induced murine hepatocarcinogenesis. Cancer Chemother Pharmacol  2020; 85(2): 331-43.
 [http://dx.doi.org/10.1007/s00280-020-04033-z] [PMID:  31989218]

[31]
Anwar H, Moghazy A, Osman A, Abdel Rahman A. The therapeutic effect of Myrrh (Commiphora molmol) and doxorubicin on diethylnitrosamine induced hepatocarcinogenesis in male albino rats. Asian Pac J Cancer Prev  2021; 22(7): 2153-63.
 [http://dx.doi.org/10.31557/APJCP.2021.22.7.2153] [PMID:  34319038]

[32]
Sepehrinezhad A, Shahbazi A, Sahab Negah S, Joghataei MT, Larsen FS. Drug-induced-acute liver failure: A critical appraisal of the thioacetamide model for the study of hepatic encephalopathy. Toxicol Rep  2021; 8: 962-70.
 [http://dx.doi.org/10.1016/j.toxrep.2021.04.011] [PMID:  34026559]

[33]
Mohi-ud-din R, Mir RH, Sawhney G, Dar MA, Bhat ZA. Possible pathways of hepatotoxicity caused by chemical agents. Curr Drug Metab  2019; 20(11): 867-79.
 [http://dx.doi.org/10.2174/1389200220666191105121653] [PMID:  31702487]

[34]
Mousa AA, El-Gansh HAI, Eldaim MAA, Mohamed MAEG, Morsi AH, El Sabagh HS. Protective effect of Moringa oleifera leaves ethanolic extract against thioacetamide-induced hepatotoxicity in rats via modulation of cellular antioxidant, apoptotic and inflammatory markers. Environ Sci Pollut Res Int  2019; 26(31): 32488-504.
 [http://dx.doi.org/10.1007/s11356-019-06368-4] [PMID:  31617137]

[35]
Kew MC. Hepatocellular carcinoma in developing countries: Prevention, diagnosis and treatment. World J Hepatol  2012; 4(3): 99-104.
 [http://dx.doi.org/10.4254/wjh.v4.i3.99] [PMID:  22489262]

[36]
Dhakal A, Hashmi MF, Sbar E. Aflatoxin toxicity. StatPearls Publishing 2023.

[37]
Pal M, Lema AG, Dame IE, Gowda L. Global public health and economic concern due to aflatoxins. Global Journal of Research in Medical Sciences  2021; 1(02)

[38]
Murcia HW, Diaz GJ. In vitro hepatic aflatoxicol production is related to a higher resistance to aflatoxin B1 in poultry. Sci Rep  2020; 10(1): 5508.
 [http://dx.doi.org/10.1038/s41598-020-62415-y] [PMID:  32218462]

[39]
Wang L, Huang Q, Wu J, et al. The metabolism and biotransformation of AFB1: Key enzymes and pathways. Biochem Pharmacol  2022; 199: 115005.
 [http://dx.doi.org/10.1016/j.bcp.2022.115005] [PMID:  35318037]

[40]
Kumara SS, Gayathri D, Hariprasad P, Venkateswaran G, Swamy CT. In vivo AFB1 detoxification by Lactobacillus fermentum LC5/a with chlorophyll and immunopotentiating activity in albino mice. Toxicon  2020; 187: 214-22.
 [http://dx.doi.org/10.1016/j.toxicon.2020.09.004] [PMID:  32941932]

[41]
Chen Y, Li R, Chang Q, Dong Z, Yang H, Xu C. Lactobacillus bulgaricus or Lactobacillus rhamnosus suppresses NF-κB signaling pathway and protects against AFB1-induced hepatitis: a novel potential preventive strategy for aflatoxicosis? Toxins (Basel)  2019; 11(1): 17.
 [http://dx.doi.org/10.3390/toxins11010017] [PMID:  30621122]

[42]
Ogemdi IK. A review on the properties and uses of paracetamol. Int J Pharm Chem  2019; 5(31.10): 11648.

[43]
Gulati K, Reshi MR, Rai N, Ray A. Hepatotoxicity: Its mechanisms, experimental evaluation and protective strategies. Am J Pharmacol  2018; 1(1): 1004.

[44]
Lee SW, Chung LS, Huang HH, Chuang TY, Liou YH, Wu LS. NAT2 and CYP2E1 polymorphisms and susceptibility to first-line anti-tuberculosis drug-induced hepatitis. Int J Tuberc Lung Dis  2010; 14(5): 622-6.
 [PMID:  20392357]

[45]
Shih TY, Young TH, Lee HS, Hsieh CB, Hu OYP. Protective effects of kaempferol on isoniazid- and rifampicin-induced hepatotoxicity. AAPS J  2013; 15(3): 753-62.
 [http://dx.doi.org/10.1208/s12248-013-9490-6] [PMID:  23591749]

[46]
Mujahid M, Siddiqui HH, Hussain A, Hussain MS. Hepatoprotective effects of Adenanthera pavonina (Linn.) against anti-tubercular drugs-induced hepatotoxicity in rats. Pharmacogn J  2013; 5(6): 286-90.
 [http://dx.doi.org/10.1016/j.phcgj.2013.08.003]

[47]
Al-Timimi ZK, Taher TA. Hepatotoxic impact of erythromycin succinate after orally repeated exposure in male albino swiss mice (Mus musculus). Iraqi J Agri Sci  2020; 51(5): 1375-80.

[48]
Bethesda L. Clinical and Research Information on Drug-Induced liver injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012. Internet

[49]
Kumar D, Rawat A, Dubey D, et al. 1 H NMR-based serum metabolomics reveals erythromycin-induced liver toxicity in albino Wistar rats. J Pharm Bioallied Sci  2016; 8(4): 327-34.
 [http://dx.doi.org/10.4103/0975-7406.199339] [PMID:  28216958]

[50]
Ricart AD. Drug-induced liver injury in Oncology. Ann Oncol  2017; 28(8): 2013-20.
 [http://dx.doi.org/10.1093/annonc/mdx158] [PMID:  28383671]

[51]
Shahid F, Farooqui Z, Khan F. Cisplatin-induced gastrointestinal toxicity: An update on possible mechanisms and on available gastroprotective strategies. Eur J Pharmacol  2018; 827: 49-57.
 [http://dx.doi.org/10.1016/j.ejphar.2018.03.009] [PMID:  29530589]

[52]
Ahmadipour A, Sharififar F, Nakhaipour F, Samanian M, Karami-Mohajeri S. Hepatoprotective effect of Zataria multiflora Boisson cisplatin-induced oxidative stress in male rat. Journal of medicine and life  2015; 8: 275.

[53]
Anderl J, Echner H, Faulstich H. Chemical modification allows phallotoxins and amatoxins to be used as tools in cell biology. Beilstein J Org Chem  2012; 8(1): 2072-84.
 [http://dx.doi.org/10.3762/bjoc.8.233] [PMID:  23209542]

[54]
Abd Rashid N, Hussan F, Hamid A, et al. Polygonum minus essential oil modulates cisplatin-induced hepatotoxicity through inflammatory and apoptotic pathways. EXCLI J  2020; 19: 1246-65.
 [PMID:  33122975]

[55]
Walton J. The cyclic peptide toxins of amanitaand other poisonous mushrooms  Available from:
          https://link.springer.com/book/10.1007/978-3-319-76822-9

[56]
Herraez E, Macias RIR, Vazquez-Tato J, Hierro C, Monte MJ, Marin JJG. Protective effect of bile acid derivatives in phalloidin-induced rat liver toxicity. Toxicol Appl Pharmacol  2009; 239(1): 21-8.
 [http://dx.doi.org/10.1016/j.taap.2009.04.017] [PMID:  19409403]

[57]
Lu YF, Liu J, Wu KC, Klaassen CD. Protection against phalloidin-induced liver injury by oleanolic acid involves Nrf2 activation and suppression of Oatp1b2. Toxicol Lett  2015; 232(1): 326-32.
 [http://dx.doi.org/10.1016/j.toxlet.2014.09.027] [PMID:  25280775]

[58]
Melaram R, Newton AR, Chafin J. Microcystin contamination and toxicity: Implications for agriculture and public health. Toxins  2022; 14(5): 350.
 [http://dx.doi.org/10.3390/toxins14050350] [PMID:  35622596]

[59]
Krishnan A, Koski G, Mou X. Characterization of microcystin-induced apoptosis in HepG2 hepatoma cells. Toxicon  2020; 173: 20-6.
 [http://dx.doi.org/10.1016/j.toxicon.2019.11.003] [PMID:  31734250]

[60]
Carvalho GMC, Oliveira VR, Casquilho NV, et al. Pulmonary and hepatic injury after sub-chronic exposure to sublethal doses of microcystin-LR. Toxicon  2016; 112: 51-8.
 [http://dx.doi.org/10.1016/j.toxicon.2016.01.066] [PMID:  26844922]

[61]
Budnik LT, Casteleyn L. Mercury pollution in modern times and its socio-medical consequences. Sci Total Environ  2019; 654: 720-34.
 [http://dx.doi.org/10.1016/j.scitotenv.2018.10.408] [PMID:  30448663]

[62]
Bernhoft RA. Mercury toxicity and treatment: A review of the literature. J Environ Public Health  2012; 2012: 460508.
 [http://dx.doi.org/10.1155/2012/460508]

[63]
Tagliafierro L, Officioso A, Sorbo S, Basile A, Manna C. The protective role of olive oil hydroxytyrosol against oxidative alterations induced by mercury in human erythrocytes. Food Chem Toxicol  2015; 82: 59-63.
 [http://dx.doi.org/10.1016/j.fct.2015.04.029] [PMID:  25957742]

[64]
Othman MS, Safwat G, Aboulkhair M, Abdel Moneim AE. The potential effect of berberine in mercury-induced hepatorenal toxicity in albino rats. Food Chem Toxicol  2014; 69: 175-81.
 [http://dx.doi.org/10.1016/j.fct.2014.04.012] [PMID:  24751971]

[65]
Rafati Rahimzadeh M, Rafati Rahimzadeh M, Kazemi S, Moghadamnia AA. Cadmium toxicity and treatment: An update. Caspian J Intern Med  2017; 8(3): 135-45.
 [PMID:  28932363]

[66]
Rikans LE, Yamano T. Mechanisms of cadmium-mediated acute hepatotoxicity. J Biochem Mol Toxicol  2000; 14(2): 110-7.
 [http://dx.doi.org/10.1002/(SICI)1099-0461(2000)14:2<110:AID-JBT7>3.0.CO;2-J] [PMID:  10630425]

[67]
Rani A, Kumar A, Lal A, Pant M. Cellular mechanisms of cadmium-induced toxicity: A review. Int J Environ Health Res  2014; 24(4): 378-99.
 [http://dx.doi.org/10.1080/09603123.2013.835032] [PMID:  24117228]

[68]
Renugadevi J, Prabu SM. Cadmium-induced hepatotoxicity in rats and the protective effect of naringenin. Exp Toxicol Pathol  2010; 62(2): 171-81.
 [http://dx.doi.org/10.1016/j.etp.2009.03.010] [PMID:  19409769]

[69]
Wani AL, Ara A, Usmani JA. Lead toxicity: A review. Interdiscip Toxicol  2015; 8(2): 55-64.
 [http://dx.doi.org/10.1515/intox-2015-0009] [PMID:  27486361]

[70]
Sangeetha KSS, Umamaheswari S. Human exposure to lead, mechanism of toxicity and treatment strategy- a review. J Clin Diagn Res  2020; 14(12)
 [http://dx.doi.org/10.7860/JCDR/2020/45615.14345]

[71]
Liu CM, Ma JQ, Sun YZ. Protective role of puerarin on lead-induced alterations of the hepatic glutathione antioxidant system and hyperlipidemia in rats. Food Chem Toxicol  2011; 49(12): 3119-27.
 [http://dx.doi.org/10.1016/j.fct.2011.09.007] [PMID:  22001170]

[72]
Zhao N, Guo FF, Xie KQ, Zeng T. Targeting Nrf-2 is a promising intervention approach for the prevention of ethanol-induced liver disease. Cell Mol Life Sci  2018; 75(17): 3143-57.
 [http://dx.doi.org/10.1007/s00018-018-2852-6] [PMID:  29947925]

[73]
Wang M, Zhu P, Jiang C, Ma L, Zhang Z, Zeng X. Preliminary characterization, antioxidant activity in vitro and hepatoprotective effect on acute alcohol-induced liver injury in mice of polysaccharides from the peduncles of Hovenia dulcis. Food Chem Toxicol  2012; 50(9): 2964-70.
 [http://dx.doi.org/10.1016/j.fct.2012.06.034] [PMID:  22750723]

[74]
Kostapanos MS, Kei A, Elisaf MS. Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease. World J Hepatol  2013; 5(9): 470-8.
 [http://dx.doi.org/10.4254/wjh.v5.i9.470] [PMID:  24073298]

[75]
Torres C, Mancinelli G, Cordoba-Chacon J, et al. p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity. Proc Natl Acad Sci  2019; 116(29): 14724-33.
 [http://dx.doi.org/10.1073/pnas.1813012116] [PMID:  31266893]

[76]
Donya M, Radford M, ElGuindy A, Firmin D, Yacoub MH. Radiation in medicine: Origins, risks and aspirations. Glob Cardiol Sci Pract  2014; 2014(4): 57.
 [http://dx.doi.org/10.5339/gcsp.2014.57] [PMID:  25780797]

[77]
Lombardini ED, Pacheco-Thompson ME. Radiation and other physical agents.  In: InHaschek and Rousseaux's Handbook of Toxicologic Pathology .  Academic Press. 2023; 3: pp. 839-927.
 [http://dx.doi.org/10.1016/B978-0-443-16153-7.00014-9]

[78]
Starkel P, Leclercq IA. Animal models for the study of hepatic fibrosis. Best Pract Res Clin Gastroenterol  2011; 25(2): 319-33.
 [http://dx.doi.org/10.1016/j.bpg.2011.02.004] [PMID:  21497748]

[79]
Sharawy MH, Abdel-Rahman N, Megahed N, El-Awady MS. Paclitaxel alleviates liver fibrosis induced by bile duct ligation in rats: Role of TGF-β1, IL-10 and c-Myc. Life Sci  2018; 211: 245-51.
 [http://dx.doi.org/10.1016/j.lfs.2018.09.037] [PMID:  30243650]

[80]
Seki E, de Minicis S, Inokuchi S, et al. CCR2 promotes hepatic fibrosis in mice. Hepatology  2009; 50(1): 185-97.
 [http://dx.doi.org/10.1002/hep.22952] [PMID:  19441102]

[81]
Vorobioff J, Bredfeldt JE, Groszmann RJ. Increased blood flow through the portal system in cirrhotic rats. Gastroenterology  1984; 87(5): 1120-6.
 [http://dx.doi.org/10.1016/S0016-5085(84)80072-4] [PMID:  6479534]

[82]
Wang X, So KF, Xu XM. Advances and challenges for neural regeneration research.  Neural Regeneration 2015; pp. 3-17.
 [http://dx.doi.org/10.1016/B978-0-12-801732-6.00001-X]

[83]
Kapila R, Kapila S, Vij R. Efficacy of milk-derived bioactive peptides on health by cellular and animal models. InNutrients in Dairy and their Implications on Health and Disease  2017; 303-11.
 [http://dx.doi.org/10.1016/B978-0-12-809762-5.00023-1]

[84]
Nevzorova YA, Boyer-Diaz Z, Cubero FJ, Gracia-Sancho J. Animal models for liver disease – A practical approach for translational research. J Hepatol  2020; 73(2): 423-40.
 [http://dx.doi.org/10.1016/j.jhep.2020.04.011] [PMID:  32330604]

[85]
Brandon EFA, Raap CD, Meijerman I, Beijnen JH, Schellens JHM. An update on in vitro test methods in human hepatic drug biotransformation research: Pros and cons. Toxicol Appl Pharmacol  2003; 189(3): 233-46.
 [http://dx.doi.org/10.1016/S0041-008X(03)00128-5] [PMID:  12791308]

[86]
Underhill GH, Khetani SR. Bioengineered liver models for drug testing and cell differentiation studies. Cell Mol Gastroenterol Hepatol  2018; 5(3): 426-439.e1.
 [http://dx.doi.org/10.1016/j.jcmgh.2017.11.012] [PMID:  29675458]

[87]
Zeilinger K, Freyer N, Damm G, Seehofer D, Knöspel F. Cell sources for in vitro human liver cell culture models. Exp Biol Med (Maywood)  2016; 241(15): 1684-98.
 [http://dx.doi.org/10.1177/1535370216657448] [PMID:  27385595]

[88]
Cavalloni G, Peraldo-Neia C, Varamo C, et al. Establishment and characterization of a human intrahepatic cholangiocarcinoma cell line derived from an Italian patient. Tumour Biol  2016; 37(3): 4041-52.
 [http://dx.doi.org/10.1007/s13277-015-4215-3] [PMID:  26486326]

[89]
Lee SML, Schelcher C, Laubender RP, et al. An algorithm that predicts the viability and the yield of human hepatocytes isolated from remnant liver pieces obtained from liver resections. PLoS One  2014; 9(10): e107567.
 [http://dx.doi.org/10.1371/journal.pone.0107567] [PMID:  25313881]

[90]
Borojevic R, Monteiro ANA, Vinhas SA, et al. Establishment of a continuous cell line from fibrotic schistosomal granulomas in mice livers. In Vitro Cell Dev Biol Plant  1985; 21(7): 382-90.
 [http://dx.doi.org/10.1007/BF02623469] [PMID:  4030623]

[91]
Schnabl B, Choi YH, Olsen JC, Hagedorn CH, Brenner DA. Immortal activated human hepatic stellate cells generated by ectopic telomerase expression. Lab Invest  2002; 82(3): 323-33.
 [http://dx.doi.org/10.1038/labinvest.3780426] [PMID:  11896211]

[92]
Vogel S, Piantedosi R, Frank J, et al. An immortalized rat liver stellate cell line (HSC-T6): A new cell model for the study of retinoid metabolism in vitro. J Lipid Res  2000; 41(6): 882-93.
 [http://dx.doi.org/10.1016/S0022-2275(20)32030-7] [PMID:  10828080]

[93]
Arzumanian VA, Kiseleva OI, Poverennaya EV. The curious case of the HepG2 cell line: 40 years of expertise. Int J Mol Sci  2021; 22(23): 13135.
 [http://dx.doi.org/10.3390/ijms222313135] [PMID:  34884942]

[94]
Sormunen R, Eskelinen S, Lehto VP. Bile canaliculus formation in cultured HEPG2 cells. Lab Invest  1993; 68(6): 652-62.
 [PMID:  8390592]

[95]
Javitt NB. Hep G2 cells as a resource for metabolic studies: Lipoprotein, cholesterol, and bile acids. FASEB J  1990; 4(2): 161-8.
 [http://dx.doi.org/10.1096/fasebj.4.2.2153592] [PMID:  2153592]

[96]
Guo L, Dial S, Shi L, et al. Similarities and differences in the expression of drug-metabolizing enzymes between human hepatic cell lines and primary human hepatocytes. Drug Metab Dispos  2011; 39(3): 528-38.
 [http://dx.doi.org/10.1124/dmd.110.035873] [PMID:  21149542]

[97]
Pareek A, Godavarthi A, Nagori BP. In vitro hepatoprotective activity of Corchorus depressus L. against CCl4 induced toxicity in HepG2 cell line. Pharmacogn J  2013; 5(4): 191-5.
 [http://dx.doi.org/10.1016/j.phcgj.2013.07.001]

[98]
Sahoo S, Rath D, Kar DM, Pattanaik S. Hepatoprotective potency of Litsea glutinosa (L.) C.B. Rob. leaf methanol extract on H2O2-induced toxicity in HepG2 cells. J Ethnopharmacol  2023; 304: 116076.
 [http://dx.doi.org/10.1016/j.jep.2022.116076] [PMID:  36567040]

[99]
Zhong J, Gastaminza P, Cheng G, et al. Robust hepatitis C virus infection in vitro. Proc Natl Acad Sci USA  2005; 102(26): 9294-9.
 [http://dx.doi.org/10.1073/pnas.0503596102] [PMID:  15939869]

[100]
Ren Z, Chen S, Ning B, Guo L. Use of liver-derived cell lines for the study of drug-induced liver injury.  Drug-Induced Liver Toxicity 2018; pp. 151-77.
 [http://dx.doi.org/10.1007/978-1-4939-7677-5_8]

[101]
Sun D, Liu J, Wang Y, Dong J. Co-administration of MDR1 and BCRP or EGFR/PI3K inhibitors overcomes lenvatinib resistance in hepatocellular carcinoma. Front Oncol  2022; 12: 944537.
 [http://dx.doi.org/10.3389/fonc.2022.944537] [PMID:  36158676]

[102]
Dongiovanni P, Crudele A, Panera N, et al. β-Klotho gene variation is associated with liver damage in children with NAFLD. J Hepatol  2020; 72(3): 411-9.
 [http://dx.doi.org/10.1016/j.jhep.2019.10.011] [PMID:  31655133]

[103]
Bartenschlager R, Sparacio S. Hepatitis C virus molecular clones and their replication capacity in vivo and in cell culture. Virus Res  2007; 127(2): 195-207.
 [http://dx.doi.org/10.1016/j.virusres.2007.02.022] [PMID:  17428568]

[104]
Steinmann E, Pietschmann T. Cell culture systems for hepatitis C virus. Hepatitis C Virus: From Molecular Virology to Antiviral Therapy  2013; 17-48.
 [http://dx.doi.org/10.1007/978-3-642-27340-7_2]

[105]
Kawamoto M, Yamaji T, Saito K, et al. Identification of characteristic genomic markers in human hepatoma HuH-7 and Huh7. 5.1-8 cell lines. Front Genet  2020; 11: 546106.
 [http://dx.doi.org/10.3389/fgene.2020.546106] [PMID:  33193621]

[106]
Mandal A, Hazra B. Medicinal plant molecules against hepatitis C virus: Current status and future prospect. Phytother Res  2023; 37(10): 4353-74.
 [http://dx.doi.org/10.1002/ptr.7936] [PMID:  37439007]

[107]
Marion MJ, Hantz O, Durantel D. The HepaRG cell line: Biological properties and relevance as a tool for cell biology, drug metabolism, and virology studies. Hepatocytes: methods and protocols   2010; 261-72.
 [http://dx.doi.org/10.1007/978-1-60761-688-7_13]

[108]
Guillouzo A, Corlu A, Aninat C, Glaise D, Morel F, Guguen-Guillouzo C. The human hepatoma HepaRG cells: A highly differentiated model for studies of liver metabolism and toxicity of xenobiotics. Chem Biol Interact  2007; 168(1): 66-73.
 [http://dx.doi.org/10.1016/j.cbi.2006.12.003] [PMID:  17241619]

[109]
Minsart C, Liefferinckx C, Lemmers A, et al. New insights in acetaminophen toxicity: HMGB1 contributes by itself to amplify hepatocyte necrosis in vitro through the TLR4-TRIF-RIPK3 axis. Sci Rep  2020; 10(1): 5557.
 [http://dx.doi.org/10.1038/s41598-020-61270-1] [PMID:  32221312]

[110]
Parent R, Marion MJ, Furio L, Trépo C, Petit MA. Origin and characterization of a human bipotent liver progenitor cell line. Gastroenterology  2004; 126(4): 1147-56.
 [http://dx.doi.org/10.1053/j.gastro.2004.01.002] [PMID:  15057753]

[111]
Guillouzo A, Guguen-Guillouzo C. HepaRG cells as a model for hepatotoxicity studies.  In: InStem Cells in Birth Defects Research and Developmental Toxicology. Hoboken, NJ, USA: John Wiley & Sons, Inc 2018.
 [http://dx.doi.org/10.1002/9781119283249.ch12]
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DOI https://dx.doi.org/10.2174/0115701638278844231214115102	Print ISSN 1570-1638
Publisher Name Bentham Science Publisher	Online ISSN 1875-6220
Current Drug Discovery Technologies

An Insight into Different Experimental Models used for Hepatoprotective Studies: A Review

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