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Current Drug Targets

Author(s): Pone Kamdem Boniface*, Fekam Boyom Fabrice*, Hugues Kamdem Paumo and Lebogang Maureen Katata-Seru

DOI: 10.2174/1389450124666221227094958

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Protective Roles and Mechanism of Action of Plant Flavonoids against Hepatic Impairment: Recent Developments

Page: [332 - 360] Pages: 29

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Abstract

Background: The liver is one of the crucial organs in humans and is responsible for the regulation of diverse processes, including metabolism, secretion, and detoxification. Ingestion of alcohol and drugs, environmental pollutants, and irradiation are among the risk factors accountable for oxidative stress in the liver. Plant flavonoids have the potential to protect the liver from damage caused by a variety of chemicals.

Objective: The present study aims to summarize up-to-date information on the protective roles of plant flavonoids against liver damage.

Methodology: The literature information on the hepatoprotective plant flavonoids was assessed through various databases, which were searched from their respective inception until March 2022.

Results: More than 70 flavonoids with hepatoprotective activity against a variety of models of liver toxicity have been reported across the literature. Among these are flavones (19), flavonols (30), flavanones (9), isoflavonoids (5), and biflavonoids (2). Several hepatoprotective mechanisms of action were reported in various classes of flavonoids, including flavones and flavonols (upregulation of the pro-survival ERK1/2 pathway; downregulation of apoptotic proteins, including Bax, Bcl-2, Bax, BH3, caspase-3, 8, 9, etc.), flavanones (downregulation of NF-κB, TNF-α, IL-1 β, IL-6, iNOS, etc.), isoflavonoids (downregulation of lipogenesis genes, such as SREBP-1c, LXRα, RXRα, PPARγ and ACC2, with concomitant upregulation of genes involved in β-oxidation, including AMPK and PPARα; inhibition of CYPs, such as CYP1A1, CYP1A2, CYP2B1, CYP2D6, CYP2E1 and CYP3A1/2).

Conclusion: The present work demonstrated the effectiveness of plant flavonoids against hepatic damage. However, more studies need to be performed regarding the cytotoxicity, pharmacokinetics, and mechanisms of action of these very important cytoprotective flavonoids.

Graphical Abstract

[1]
Madrigal-Santillán E, Madrigal-Bujaidar E, Álvarez-González I, et al. Review of natural products with hepatoprotective effects. World J Gastroenterol 2014; 20(40): 14787-804.
[http://dx.doi.org/10.3748/wjg.v20.i40.14787] [PMID: 25356040]
[2]
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.
[http://dx.doi.org/10.1016/j.phymed.2021.153479] [PMID: 33561764]
[3]
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): 26087-124.
[http://dx.doi.org/10.3390/ijms161125942] [PMID: 26540040]
[4]
Yamamoto H, Kanno K, Ikuta T, et al. Enhancing hepatic fibrosis in spontaneously hypertensive rats fed a choline-deficient diet: a follow-up report on long-term effects of oxidative stress in non-alcoholic fatty liver disease. J Hepatobiliary Pancreat Sci 2016; 23(5): 260-9.
[http://dx.doi.org/10.1002/jhbp.333] [PMID: 26880573]
[5]
Zhang X, Gao X, Long G, et al. Lanostane-type triterpenoids from the mycelial mat of Ganoderma lucidum and their hepatoprotective activities. Phytochemistry 2022; 198: 113131.
[http://dx.doi.org/10.1016/j.phytochem.2022.113131] [PMID: 35248578]
[6]
Shi C, Wang J, Zhang R, et al. Dihydromyricetin alleviates Escherichia coli lipopolysaccharide-induced hepatic injury in chickens by inhibiting the NLRP3 inflammasome. Vet Res 2022; 53(1): 6.
[http://dx.doi.org/10.1186/s13567-022-01024-1] [PMID: 35073994]
[7]
Lin X, Huang R, Zhang S, et al. Methyl helicterate protects against CCl4-induced liver injury in rats by inhibiting oxidative stress, NF-κB activation, Fas/FasL pathway and cytochrome P4502E1 level. Food Chem Toxicol 2012; 50(10): 3413-20.
[http://dx.doi.org/10.1016/j.fct.2012.07.053] [PMID: 22889900]
[8]
Ben Saad A, Dalel B, Rjeibi I, et al. Phytochemical, antioxidant and protective effect of Cactus cladodes extract against lithium-induced liver injury in rats. Pharm Biol 2017; 55(1): 516-25.
[http://dx.doi.org/10.1080/13880209.2016.1255976] [PMID: 27951739]
[9]
Somade OT, Ajayi BO, Olunaike OE, Jimoh LA. Hepatic oxidative stress, up-regulation of pro-inflammatory cytokines, apoptotic and oncogenic markers following 2-methoxyethanol administrations in rats. Biochem Biophys Rep 2020; 24: 100806.
[http://dx.doi.org/10.1016/j.bbrep.2020.100806] [PMID: 32913901]
[10]
Baradaran A, Samadi F, Ramezanpour SS, Yousefdoust S. Hepatoprotective effects of silymarin on CCl4-induced hepatic damage in broiler chickens model. Toxicol Rep 2019; 6: 788-94.
[http://dx.doi.org/10.1016/j.toxrep.2019.07.011] [PMID: 31440455]
[11]
Burgess CA. Silybum marianum (Milk Thistle). J Pharm Soc Wincons 2003; 38-40.
[12]
Soleimani V, Delghandi PS, Moallem SA, Karimi G. Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review. Phytother Res 2019; 33(6): 1627-38.
[http://dx.doi.org/10.1002/ptr.6361] [PMID: 31069872]
[13]
Fallahzadeh MK, Dormanesh B, Sagheb MM, et al. Effect of addition of silymarin to renin-angiotensin system inhibitors on proteinuria in type 2 diabetic patients with overt nephropathy: A randomized, double-blind, placebo-controlled trial. Am J Kidney Dis 2012; 60(6): 896-903.
[http://dx.doi.org/10.1053/j.ajkd.2012.06.005] [PMID: 22770926]
[14]
Di Pierro F, Bellone I, Rapacioli G, Putignano P. Clinical role of a fixed combination of standardized Berberis aristata and Silybum marianum extracts in diabetic and hypercholesterolemic patients intolerant to statins. Diabetes Metab Syndr Obes 2015; 8: 89-96.
[http://dx.doi.org/10.2147/DMSO.S78877] [PMID: 25678808]
[15]
Zhang HY, Wang HL, Zhong GY, Zhu JX. Molecular mechanism and research progress on pharmacology of traditional Chinese medicine in liver injury. Pharm Biol 2018; 56(1): 594-611.
[http://dx.doi.org/10.1080/13880209.2018.1517185] [PMID: 31070528]
[16]
Dhiman A, Nanda A, Ahmad S. A quest for staunch effects of flavonoids: Utopian protection against hepatic ailments. Arab J Chem 2016; 9: S1813-23.
[http://dx.doi.org/10.1016/j.arabjc.2012.05.001]
[17]
Gebhardt R, Fausel M. Antioxidant and hepatoprotective effects of artichoke extracts and constituents in cultured rat hepatocytes. Toxicol In Vitro 1997; 11(5): 669-72.
[http://dx.doi.org/10.1016/S0887-2333(97)00078-7] [PMID: 20654368]
[18]
Lee HU, Bae EA, Kim DH. Hepatoprotective effect of tectoridin and tectorigenin on tert-butyl hyperoxide-induced liver injury. J Pharmacol Sci 2005; 97(4): 541-4.
[http://dx.doi.org/10.1254/jphs.SCZ040467] [PMID: 15821336]
[19]
Kim SM, Kang K, Jho EH, et al. Hepatoprotective effect of flavonoid glycosides from Lespedeza cuneata against oxidative stress induced by tert-butyl hyperoxide. Phytother Res 2011; 25(7): 1011-7.
[http://dx.doi.org/10.1002/ptr.3387] [PMID: 21226126]
[20]
Jung JW, Ko WM, Park JH, et al. Isoprenylated flavonoids from the root bark of Morus alba and their hepatoprotective and neuroprotective activities. Arch Pharm Res 2015; 38(11): 2066-75.
[http://dx.doi.org/10.1007/s12272-015-0613-8] [PMID: 25981820]
[21]
Jung HA, Abdul QA, Byun JS, et al. Protective effects of flavonoids isolated from Korean milk thistle Cirsium japonicum var. maackii (Maxim.) Matsum on tert -butyl hydroperoxide-induced hepatotoxicity in HepG2 cells. J Ethnopharmacol 2017; 209: 62-72.
[http://dx.doi.org/10.1016/j.jep.2017.07.027] [PMID: 28735729]
[22]
Kalantari H, Foruozandeh H, Khodayar MJ, Siahpoosh A, Saki N, Kheradmand P. Antioxidant and hepatoprotective effects of Capparis spinosa L. fractions and Quercetin on tert-butyl hydroperoxide- induced acute liver damage in mice. J Tradit Complement Med 2018; 8(1): 120-7.
[http://dx.doi.org/10.1016/j.jtcme.2017.04.010] [PMID: 29321999]
[23]
Closa D, Torres M, Hotter G, et al. Prostanoids and free radicals in Cl4C-induced hepatotoxicity in rats: Effect of astilbin. Prostaglandins Leukot Essent Fatty Acids 1997; 56(4): 331-4.
[http://dx.doi.org/10.1016/S0952-3278(97)90578-0] [PMID: 9150380]
[24]
Perez Gutierrez RM, Anaya sosa I, Hoyo Vadillo C, Victoria TC. Effect of flavonoids from Prosthechea michuacana on carbon tetrachloride induced acute hepatotoxicity in mice. Pharm Biol 2011; 49(11): 1121-7.
[http://dx.doi.org/10.3109/13880209.2011.570766] [PMID: 22014261]
[25]
Domitrović R, Jakovac H, Vasiljev Marchesi V, et al. Differential hepatoprotective mechanisms of rutin and quercetin in CCl4-intoxicated BALB/cN mice. Acta Pharmacol Sin 2012; 33(10): 1260-70.
[http://dx.doi.org/10.1038/aps.2012.62] [PMID: 22902988]
[26]
Cho BO, Ryu HW, So Y, et al. Hepatoprotective effect of 2,3-dehydrosilybin on carbon tetrachloride-induced liver injury in rats. Food Chem 2013; 138(1): 107-15.
[http://dx.doi.org/10.1016/j.foodchem.2012.10.026] [PMID: 23265463]
[27]
Hermenean A, Ardelean A, Stan M, et al. Antioxidant and hepatoprotective effects of naringenin and its β-cyclodextrin formulation in mice intoxicated with carbon tetrachloride: A comparative study. J Med Food 2014; 17(6): 670-7.
[http://dx.doi.org/10.1089/jmf.2013.0007] [PMID: 24611872]
[28]
Ji LL, Sheng YC, Zheng ZY, Shi L, Wang ZT. The involvement of p62–Keap1–Nrf2 antioxidative signaling pathway and JNK in the protection of natural flavonoid quercetin against hepatotoxicity. Free Radic Biol Med 2015; 85: 12-23.
[http://dx.doi.org/10.1016/j.freeradbiomed.2015.03.035] [PMID: 25881548]
[29]
Nagaraja YP, Krishna V. Hepatoprotective effect of the aqueous extract and 5-hydroxy, 7,8,2′-trimethoxy flavone of Andrographis alata Nees in carbon tetrachloride treated rats. Achievements in the Life Sciences 2016; 10(1): 5-10.
[http://dx.doi.org/10.1016/j.als.2016.05.002]
[30]
Nguyen TP, Tran CL, Vuong CH, et al. Flavonoids with hepatoprotective activity from the leaves of Cleome viscosa L. Nat Prod Res 2017; 31(22): 2587-92.
[http://dx.doi.org/10.1080/14786419.2017.1283497] [PMID: 28135851]
[31]
Kokanova-Nedialkova Z, Nedialkov P, Kondeva-Burdina M, Simeonova R, Tzankova V, Aluani D. Chenopodium bonus - henricus L. – A source of hepatoprotective flavonoids. Fitoterapia 2017; 118: 13-20.
[http://dx.doi.org/10.1016/j.fitote.2017.02.001] [PMID: 28229939]
[32]
Kondeva-Burdina M, Shkondrov A, Simeonova R, Vitcheva V, Krasteva I, Ionkova I. In vitro/in vivo antioxidant and hepatoprotective potential of defatted extract and flavonoids isolated from Astragalus spruneri Boiss (Fabaceae). Food Chem Toxicol 2018; 111: 631-40.
[http://dx.doi.org/10.1016/j.fct.2017.12.020] [PMID: 29247771]
[33]
Yang YN, Liu YY, Feng ZM, Jiang JS, Zhang PC. Seven new flavonoid glycosides from the roots of Glycyrrhiza uralensis and their biological activities. Carbohydr Res 2019; 485: 107820.
[http://dx.doi.org/10.1016/j.carres.2019.107820] [PMID: 31546144]
[34]
El-Aarag B, Khairy A, Khalifa SAM, El-Seedi HR. Protective effects of flavone from Tamarix aphylla against CCl4-induced liver injury in mice mediated by suppression of oxidative stress, apoptosis and angiogenesis. Int J Mol Sci 2019; 20(20): 5215.
[http://dx.doi.org/10.3390/ijms20205215] [PMID: 31640181]
[35]
Wei R, Ma Q, Zhong G, He J, Sang Z. Isolation and characterization of flavonoid derivatives with anti-prostate cancer and hepatoprotective activities from the flowers of Hosta plantaginea (Lam.) Aschers. J Ethnopharmacol 2020; 253: 112685.
[http://dx.doi.org/10.1016/j.jep.2020.112685] [PMID: 32101774]
[36]
Yoshikawa M, Xu F, Morikawa T, Ninomiya K, Matsuda H. Anastatins A and B, new skeletal flavonoids with hepatoprotective activities from the desert plant Anastatica hierochuntica. Bioorg Med Chem Lett 2003; 13(6): 1045-9.
[http://dx.doi.org/10.1016/S0960-894X(03)00088-X] [PMID: 12643908]
[37]
Matsuda H, Morikawa T, Xu F, Ninomiya K, Yoshikawa M. New isoflavones and pterocarpane with hepatoprotective activity from the stems of Erycibe expansa. Planta Med 2004; 70(12): 1201-9.
[http://dx.doi.org/10.1055/s-2004-835852] [PMID: 15643558]
[38]
Pushpavalli G, Veeramani C, Pugalendi KV. Influence of chrysin on hepatic marker enzymes and lipid profile against d-galactosamine-induced hepatotoxicity rats. Food Chem Toxicol 2010; 48(6): 1654-9.
[http://dx.doi.org/10.1016/j.fct.2010.03.040] [PMID: 20362027]
[39]
Ma Q, Guo Y, Wei R, et al. Flavonoids from Capsella bursa-pastoris and their hepatoprotective activities in vitro Brazil. J Pharmacol 2016; 26: 710-3.
[40]
Lv H, An B, Yu Q, Cao Y, Liu Y, Li S. The hepatoprotective effect of myricetin against lipopolysaccharide and D-galactosamine-induced fulminant hepatitis. Int J Biol Macromol 2020; 155: 1092-104.
[http://dx.doi.org/10.1016/j.ijbiomac.2019.11.075] [PMID: 31712142]
[41]
He Y, Xia Z, Yu D, et al. Hepatoprotective effects and structure-activity relationship of five flavonoids against lipopolysaccharide/d-galactosamine induced acute liver failure in mice. Int Immunopharmacol 2019; 68: 171-8.
[http://dx.doi.org/10.1016/j.intimp.2018.12.059] [PMID: 30641432]
[42]
Al-Anati L, Essid E, Reinehr R, Petzinger E. Silibinin protects OTA-mediated TNF-α release from perfused rat livers and isolated rat Kupffer cells. Mol Nutr Food Res 2009; 53(4): 460-6.
[http://dx.doi.org/10.1002/mnfr.200800110] [PMID: 19156713]
[43]
de Souza CO, Peraçoli MTS, Weel IC, et al. Hepatoprotective and anti-inflammatory effects of silibinin on experimental preeclampsia induced by l-NAME in rats. Life Sci 2012; 91(5-6): 159-65.
[http://dx.doi.org/10.1016/j.lfs.2012.06.036] [PMID: 22781706]
[44]
Jang SI, Kim HJ, Hwang KM, et al. Hepatoprotective effect of baicalin, a major flavone from Scutellaria radix, on acetaminophen-induced liver injury in mice. Immunopharmacol Immunotoxicol 2003; 25(4): 585-94.
[http://dx.doi.org/10.1081/IPH-120026443] [PMID: 14686800]
[45]
Akachi T, Shiina Y, Ohishi Y, et al. Hepatoprotective effects of flavonoids from shekwasha (Citrus depressa) against D-galactosamine-induced liver injury in rats. J Nutr Sci Vitaminol (Tokyo) 2010; 56(1): 60-7.
[http://dx.doi.org/10.3177/jnsv.56.60] [PMID: 20354348]
[46]
Wu KC, Ho Y-L, Kuo Y-H, Huang S-S, Huang G-J, Chang Y-S. Ho. Y.-L.; Kuo, Y.-H.; Huang, S.-S.; Huang, G.-J.; Chang, Y.-S. Hepatoprotective effect of ugonin M, a Helminthostachys zeylanica constituent, on acetaminophen-induced acute liver injury in mice. Molecules 2018; 23(10): 2420.
[http://dx.doi.org/10.3390/molecules23102420]
[47]
Liu Q, Pan R, Ding L, et al. Rutin exhibits hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease by reducing hepatic lipid levels and mitigating lipid-induced oxidative injuries. Int Immunopharmacol 2017; 49: 132-41.
[http://dx.doi.org/10.1016/j.intimp.2017.05.026] [PMID: 28577437]
[48]
Toppo E, Darvin SS, Esakkimuthu S, et al. Antihyperlipidemic and hepatoprotective effects of Gardenin A in cellular and high fat diet fed rodent models. Chem Biol Interact 2017; 269: 9-17.
[http://dx.doi.org/10.1016/j.cbi.2017.03.013] [PMID: 28351695]
[49]
Su X, Li L, Sun H, et al. Eight new glycosides with hepatoprotective activity isolated from the aerial parts of Morinda parvifolia. Bioorg Chem 2019; 87: 867-75.
[http://dx.doi.org/10.1016/j.bioorg.2018.11.055] [PMID: 30528930]
[50]
Mohammadi A, Kazemi S, Hosseini M, et al. Chrysin effect in prevention of acetaminophen-induced hepatotoxicity in rat. Chem Res Toxicol 2019; 32(11): 2329-37.
[http://dx.doi.org/10.1021/acs.chemrestox.9b00332] [PMID: 31625388]
[51]
Ma Q, Wei R, Sang Z, Dong J. Structural characterization, neuroprotective and hepatoprotective activities of flavonoids from the bulbs of Heleocharis dulcis. Bioorg Chem 2020; 96: 103630.
[http://dx.doi.org/10.1016/j.bioorg.2020.103630] [PMID: 32036163]
[52]
Shankari SG, Karthikesan K, Jalaludeen AM, Ashokkumar N. Hepatoprotective effect of morin on ethanol-induced hepatotoxicity in rats. J Basic Clin Physiol Pharmacol 2010; 21(4): 277-94.
[http://dx.doi.org/10.1515/JBCPP.2010.21.4.277] [PMID: 21305846]
[53]
Wang M, Sun J, Jiang Z, Xie W, Zhang X. Hepatoprotective effect of kaempferol against alcoholic liver injury in mice. Am J Chin Med 2015; 43(2): 241-54.
[http://dx.doi.org/10.1142/S0192415X15500160] [PMID: 25787296]
[54]
Singaravelu A, Venkatachalam K, Jayaraj RL, Jayabalan P, Nadanam S. Morin treatment for acute ethanol exposure in rats. Biotech Histochem 2021; 96(3): 230-41.
[http://dx.doi.org/10.1080/10520295.2020.1785548] [PMID: 32597243]
[55]
Morel I, Lescoat G, Cogrel P, et al. Antioxidant and iron-chelating activities of the flavonoids catechin, quercetin and diosmetin on iron-loaded rat hepatocyte cultures. Biochem Pharmacol 1993; 45(1): 13-9.
[http://dx.doi.org/10.1016/0006-2952(93)90371-3] [PMID: 8424806]
[56]
Oh H, Kim D-H, Cho J-H, Kim Y-C. Hepatoprotective and free radical scavenging activities of phenolic petrosins and flavonoids isolated from Equisetum arvense. J Ethnopharmacol 2004; 95(2-3): 421-4.
[http://dx.doi.org/10.1016/j.jep.2004.08.015] [PMID: 15507369]
[57]
Matić S, Stanić S, Bogojević D, et al. Methanol extract from the stem of Cotinus coggygria Scop., and its major bioactive phytochemical constituent myricetin modulate pyrogallol-induced DNA damage and liver injury. Mutat Res Genet Toxicol Environ Mutagen 2013; 755(2): 81-9.
[http://dx.doi.org/10.1016/j.mrgentox.2013.03.011] [PMID: 23830930]
[58]
Lin SY, Wang YY, Chen WY, Chuang YH, Pan PH, Chen CJ. Beneficial effect of quercetin on cholestatic liver injury. J Nutr Biochem 2014; 25(11): 1183-95.
[http://dx.doi.org/10.1016/j.jnutbio.2014.06.003] [PMID: 25108658]
[59]
Arivazhagan L, Subramanian SP. Tangeretin, a citrus flavonoid attenuates oxidative stress and protects hepatocellular architecture in rats with 7, 12 - dimethylbenz(a)anthracene induced experimental mammary carcinoma. J Funct Foods 2015; 15: 339-53.
[http://dx.doi.org/10.1016/j.jff.2015.03.041]
[60]
Ansar S, Siddiqi NJ, Zargar S, Ganaie MA, Abudawood M. Hepatoprotective effect of Quercetin supplementation against Acrylamide-induced DNA damage in wistar rats. BMC Complement Altern Med 2016; 16(1): 327.
[http://dx.doi.org/10.1186/s12906-016-1322-7] [PMID: 27576905]
[61]
Yin H, Huang L, Ouyang T, Chen L. Baicalein improves liver inflammation in diabetic db/db mice by regulating HMGB1/TLR4/NF-κB signaling pathway. Int Immunopharmacol 2018; 55: 55-62.
[http://dx.doi.org/10.1016/j.intimp.2017.12.002] [PMID: 29223854]
[62]
Ge L, Li J, Wan H, et al. Novel flavonoids from Lonicera japonica flower buds and validation of their anti-hepatoma and hepatoprotective activity in vitro studies. Ind Crops Prod 2018; 125: 114-22.
[http://dx.doi.org/10.1016/j.indcrop.2018.08.073]
[63]
Lu X, Liu T, Chen K, et al. Isorhamnetin: A hepatoprotective flavonoid inhibits apoptosis and autophagy via P38/PPAR-α pathway in mice. Biomed Pharmacother 2018; 103: 800-11.
[http://dx.doi.org/10.1016/j.biopha.2018.04.016] [PMID: 29684859]
[64]
Šuk J, Jašprová J, Biedermann D, et al. Isolated silymarin flavonoids increase systemic and hepatic bilirubin concentrations and lower lipoperoxidation in mice. Oxid Med Cell Longev 2019; 2019: 1-12.
[http://dx.doi.org/10.1155/2019/6026902] [PMID: 30891115]
[65]
Lee IC, Bae JS. Hepatoprotective effects of vicenin-2 and scolymoside through the modulation of inflammatory pathways. J Nat Med 2020; 74(1): 90-7.
[http://dx.doi.org/10.1007/s11418-019-01348-x] [PMID: 31350693]
[66]
Cui S, Pan XJ, Ge CL, et al. Silybin alleviates hepatic lipid accumulation in methionine-choline deficient diet-induced nonalcoholic fatty liver disease in mice via peroxisome proliferator-activated receptor α. Chin J Nat Med 2021; 19(6): 401-11.
[http://dx.doi.org/10.1016/S1875-5364(21)60039-0] [PMID: 34092291]
[67]
Boniface PK, Elizabeth FI. Flavonoid-derived privileged scaffolds in anti-Trypanosoma cruzi drug discovery. Curr Drug Targets 2019; 20(12): 1295-314.
[http://dx.doi.org/10.2174/1389450120666190618114857] [PMID: 31215385]
[68]
Boniface PK, Ferreira EI. Opportunities and challenges for flavonoids as potential leads for the treatment of tuberculosis. Studies in Natural Products Chemistry 2020; 65: 85-124.
[http://dx.doi.org/10.1016/B978-0-12-817905-5.00003-2]
[69]
Boniface PK, Ferreira EI. Flavonoids as efficient scaffolds: Recent trends for malaria, leishmaniasis, Chagas disease, and dengue. Phytother Res 2019; 33(10): 2473-517. b
[http://dx.doi.org/10.1002/ptr.6383] [PMID: 31441148]
[70]
Fu S, Wu D, Jiang W, et al. Molecular biomarkers in drug-induced liver injury: Challenges and future perspectives. Front Pharmacol 2020; 10: 1667.
[http://dx.doi.org/10.3389/fphar.2019.01667] [PMID: 32082163]
[71]
Yang X, Schnackenberg LK, Shi Q, Salminen WF. Hepatic toxicity biomarkers. Review of existing biomarkers of liver toxicity. In: Gupta R (Ed.). Elsevier, 2014; pp. 241-59.
[72]
Rana P, Aleo MD, Wen X, Kogut S. Hepatotoxicity reports in the FDA adverse event reporting system database: A comparison of drugs that cause injury via mitochondrial or other mechanisms. Acta Pharm Sin B 2021; 11(12): 3857-68.
[http://dx.doi.org/10.1016/j.apsb.2021.05.028] [PMID: 35024312]
[73]
Babai S, Auclert L, Le-Louët H. Safety data and withdrawal of hepatotoxic drugs. Therapie 2021; 76(6): 715-23.
[http://dx.doi.org/10.1016/j.therap.2018.02.004] [PMID: 29609830]
[74]
A.F.; Alharbi, M.; Alqahtani, F.; Alasmari, F.; AlSwayyed, M.; Alzarea, S.I.; AI-Alallah, I.A.; Alghamdi, A.; Hakami, H.; Alyousef, M.K. 2021. Diosmin alleviates doxorubicin-induced liver injury via modulation and apoptosis via NfkB and MAPK pathway: A preclinical study. Antioxidants 2021; 10: 1-16.
[75]
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]
[76]
Al-Sayed E, Abdel-Daim MM, Kilany OE, Karonen M, Sinkkonen J. Protective role of polyphenols from Bauhinia hookeri against carbon tetrachloride-induced hepato- and nephrotoxicity in mice. Ren Fail 2015; 37(7): 1198-207.
[http://dx.doi.org/10.3109/0886022X.2015.1061886] [PMID: 26382171]
[77]
Weber LWD, Boll M, Stampfl A. Hepatotoxicity and mechanism of action of haloalkanes: Carbon tetrachloride as a toxicological model. Crit Rev Toxicol 2003; 33(2): 105-36.
[http://dx.doi.org/10.1080/713611034] [PMID: 12708612]
[78]
Bhavsar SK, Joshi P, Shah MB, Santani DD. Investigation into hepatoprotective activity of Citrus limon. Pharm Biol 2007; 45(4): 303-11.
[http://dx.doi.org/10.1080/13880200701214995]
[79]
Al-Sayed E, Abdel-Daim M. Protective role of Cupressuflavone from Cupressus macrocarpa against carbon tetrachloride-induced hepato- and nephrotoxicity in mice. Planta Med 2014; 80(18): 1665-71.
[http://dx.doi.org/10.1055/s-0034-1383211] [PMID: 25338212]
[80]
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: 1-12.
[http://dx.doi.org/10.1155/2014/752506] [PMID: 24847414]
[81]
Quintero A, Pedraza CA, Siendones E, et al. PGE1 protection against apoptosis induced by D-galactosamine is not related to the modulation of intracellular free radical production in primary culture of rat hepatocytes. Free Radic Res 2002; 36(3): 345-55.
[http://dx.doi.org/10.1080/10715760290019372] [PMID: 12071354]
[82]
Luyendyk JP, Roth RA, Ganey PE. Inflammation and hepatotoxicity. Comprehensive Toxicology (Second Edition) 2010; 9: 295-317.
[http://dx.doi.org/10.1016/B978-0-08-046884-6.01031-9]
[83]
Hinson JA, Roberts DW, James LP. Mechanisms of acetaminophen-induced liver necrosis. Handb Exp Pharmacol 2010; 196(196): 369-405.
[http://dx.doi.org/10.1007/978-3-642-00663-0_12] [PMID: 20020268]
[84]
Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ. Mechanisms of hepatotoxicity. Toxicol Sci 2002; 65(2): 166-76.
[http://dx.doi.org/10.1093/toxsci/65.2.166] [PMID: 11812920]
[85]
Cichoż-Lach H, Michalak A. Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol 2014; 20(25): 8082-91.
[http://dx.doi.org/10.3748/wjg.v20.i25.8082] [PMID: 25009380]
[86]
Cho BO, Kim JH, Che DN, et al. Kushenol C prevents tert-butyl hydroperoxide and acetaminophen-induced liver injury. Molecules 2021; 26(6): 1635.
[http://dx.doi.org/10.3390/molecules26061635] [PMID: 33804228]
[87]
Liang F, Fang Y, Cao W, Zhang Z, Pan S, Xu X. Attenuation of tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in HepG2 cells by tangeritin: Relevance of the Nrf2-ARE and MAPK signaling pathways. J Agric Food Chem 2018; 66(25): 6317-25.
[http://dx.doi.org/10.1021/acs.jafc.8b01875] [PMID: 29871486]
[88]
Suraweera TL, Rupasinghe V, Dellaire G, Xu Z. Regulation of Nrf/ARE pathway by dietary flavonoids: A friend of foe for cancer management? Antioxidants 2020; 9: 1-44.
[http://dx.doi.org/10.3390/antiox9100973]
[89]
Aherne SA, O’Brien NM. Mechanism of protection by the flavonoids, quercetin and rutin, against tert-butylhydroperoxide- and menadione-induced DNA single strand breaks in Caco-2 cells. Free Radic Biol Med 2000; 29(6): 507-14.
[http://dx.doi.org/10.1016/S0891-5849(00)00360-9] [PMID: 11025194]
[90]
Lv H, Ren H, Wang L, Chen W, Ci X. Lico A enhances Nrf2-mediated defense mechanisms against t-BHP-induced oxidative stress and cell death via Akt and ERK activation in Raw264.7 cells. Oxid Med Cell Longev 2015; 2015: 1-13.
[http://dx.doi.org/10.1155/2015/709845] [PMID: 26576227]
[91]
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(6): 663-9.
[http://dx.doi.org/10.1089/jmf.2013.2834] [PMID: 24712752]
[92]
Pérez-Trueba G, Ramos-Guanche C, Martínez-Sánchez B, Márquez-Hernández I, Giuliani A, Martínez-Sánchez G. Protective effect of Gossypitrin on carbon tetrachloride-induced in vivo hepatotoxicity. Redox Rep 2003; 8(4): 215-21.
[http://dx.doi.org/10.1179/135100003225002718] [PMID: 14599345]
[93]
Lin Y, Luo H, Wang X, et al. Flavanones from Sedum sarmentosum Bunge alleviate CCl4-induced liver fibrosis in rats by targeting TGF-β1/TβR/Smad pathway in turn inhibiting epithelial mesenchymal transition. Evid Based Complement Alternat Med 2018; 2018: 1-10.
[http://dx.doi.org/10.1155/2018/3080837]
[94]
Perrissoud D, Testa B. Inhibiting or potentiating effects of flavonoids on carbon tetrachloride-induced toxicity in isolated rat hepatocytes. Arzneimittelforschung 1986; 36(8): 1249-53.
[PMID: 3778562]
[95]
Apte U. Galactosamine. Encyclopedia of Toxicology. (3rd ed.). 2014; pp. 689-90.
[96]
Wańkowicz Z, Zdanowski R, Brytan M, et al. D-Galactosamine intoxication in experimental animals: Is it only an experimental model of acute liver failure? Med Sci Monit 2015; 21: 1469-77.
[http://dx.doi.org/10.12659/MSM.893291] [PMID: 26009004]
[97]
Pu Y, Yang Z, Mo X. Protective effect of luteolin on D-galactosamine (D-Gal)/lipopolysaccharide (LPS) induced hepatic injury by in mice. BioMed Res Int 2021; 2021: 1-8.
[http://dx.doi.org/10.1155/2021/2252705] [PMID: 34368345]
[98]
Wada S, He P, Hashimoto I, Watanabe N, Sugiyama K. Glycosidic flavonoids as rat-liver injury preventing compounds from green tea. Biosci Biotechnol Biochem 2000; 64(10): 2262-5.
[http://dx.doi.org/10.1271/bbb.64.2262] [PMID: 11129610]
[99]
Liu J. Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol 1995; 49(2): 57-68.
[http://dx.doi.org/10.1016/0378-8741(95)90032-2] [PMID: 8847885]
[100]
Cao L, Kwara A, Greenblatt DJ. Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol 2017; 69(12): 1762-72.
[http://dx.doi.org/10.1111/jphp.12812] [PMID: 28872689]
[101]
BinMowyna MN, AlFaris NA. Kaempferol suppresses acetaminophen-induced liver damage by upregulation/activation of SIRT1. Pharm Biol 2021; 59(1): 144-54.
[http://dx.doi.org/10.1080/13880209.2021.1877734]
[102]
Yousefdoost S, Samadi F, Jafari SM, Ramezanpour SS, Hassani S, Ganji F. Application of nanoencapsulated silymarin to improve its antioxidant and hepatoprotective activities against carbon tetrachloride-induced oxidative stress in broiler chickens. Livest Sci 2019; 228: 177-86.
[http://dx.doi.org/10.1016/j.livsci.2019.08.015]
[103]
Tzankova V, Aluani D, Kondeva-Burdina M, et al. Hepatoprotective and antioxidant activity of quercetin loaded chitosan/alginate particles in vitro and in vivo in a model of paracetamol-induced toxicity. Biomed Pharmacother 2017; 92: 569-79.
[http://dx.doi.org/10.1016/j.biopha.2017.05.008] [PMID: 28577496]
[104]
Thant Y, Wang Q, Wei C, et al. TPGS conjugated pro-liposomal nano-drug delivery system potentiate the antioxidant and hepatoprotective activity of Myricetin. J Drug Deliv Sci Technol 2021; 66: 102808.
[http://dx.doi.org/10.1016/j.jddst.2021.102808]
[105]
Valenzuela A, Garrido A. Biochemical bases of the pharmacological action of the flavonoid silymarin and of its structural isomer silibinin. Biol Res 1994; 27(2): 105-12.
[PMID: 8640239]
[106]
Xie W, Wang M, Chen C, Zhang X, Melzig MF. Hepatoprotective effect of isoquercitrin against acetaminophen-induced liver injury. Life Sci 2016; 152: 180-9.
[http://dx.doi.org/10.1016/j.lfs.2016.04.002] [PMID: 27049115]