Traditional Medicinal Plants with Significant Protection Against Antitubercular Drug-induced Liver Injury: A Systematic Review

Abstract

Background and objectives

Tuberculosis remains a global health concern, and its treatment usually involves potent first-line antitubercular drugs which are tempered by the risk of associated hepatotoxicity leading to noncompliance and drug resistance. In this review, medicinal plants with the potential of protection against antitubercular drug-induced hepatotoxicity in animal models were explored from scientific literatures.

Methods From literature published between 1999 and 2022, this review systematically extracted 68 studies that reported on medicinal plants with protection against antitubercular drug-induced liver toxicity in animal models.

Results Isoniazid, pyrazinamide, rifampicin, and etambutol were the first-line drugs reported in the reviewed studies. The liver enzymes, antioxidant status, inflammatory markers, and improvement in the liver architecture were the criteria most frequently used by the reported studies to access hepatoprotection. These plants are rich in bioactive phytochemicals which exhibit their hepatoprotective properties via mechanisms such as antioxidant activity, anti-inflammatory effects, and detoxification enhancement.

Conclusions This review provides the hepatoprotective properties and mode of action of medicinal plants and encourages future perspectives marked by rigorous scientific research, clinical trials, and integrative medicine approaches. Albeit the challenges of standardization of herbal formulation, safety concerns and hurdles of the regulatory framework must be addressed as traditional medicinal plants offer a promise to mitigate antitubercular drug hepatotoxicity.

Keywords

Antitubercular drugs / Medicinal plants / Hepatoprotective / Toxicity

Acknowledgments

The authors have no acknowledgements.

Funding

This paper was not supported by any specified funding.

Conflict of interest

The authors declare they have no real or potential conflict of inter-ests related to this paper.

Author contributions

Conceived the idea and wrote the initial draft (CEU), and per-formed the literature search and data collection (SMS). Both au-thors proofread the final manuscript.

Data sharing statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

[1] Molla Y, Wubetu M, Dessie B. Anti-Tuberculosis Drug Induced Hepa-totoxicity and Associated Factors among Tuberculosis Patients at Selected Hospitals, Ethiopia. Hepat Med 2021; 13:1-8. doi:10.2147/HMER.S290542,PMID:33536799.

[2] Sanni S, Sina H, Baba-Moussa L. Genetic polymorphisms and tox-icities of first-line antituberculosis drugs: systematic review of the literature. J Tubercul Res 2022; 10(3):124-145. doi:10.4236/jtr.2022.103010.

[3] Dartois VA, Rubin EJ. Anti-tuberculosis treatment strategies and drug development: challenges and priorities. Nat Rev Microbiol 2022; 20(11):685-701. doi:10.1038/s41579-022-00731-y,PMID:35478222.

[4] Villar-Hernández R, Ghodousi A, Konstantynovska O, Duarte R, Lange C, Raviglione M. Tuberculosis: current challenges and beyond. Breathe (Sheff) 2023; 19(1):220166. doi:10.1183/20734735.0166-2022,PMID:37334103.

[5] World Health Organization.Global tuberculosis report 2022. Geneva: World Health organization; 2022.

[6] Kerantzas CA, Jacobs WR Jr. Origins of Combination Therapy for Tu-berculosis: Lessons for Future Antimicrobial Development and Ap-plication. mBio 2017; 8(2):e01586-16. doi:10.1128/mBio.01586-16.PubMed, PMID:28292983.

[7] Jaramillo-Valverde L, Levano KS, Tarazona DD, Vasquez-Dominguez A, Toledo-Nauto A, Capristano S, et al. GSTT1/GSTM1 Genotype and Anti-Tuberculosis Drug-Induced Hepatotoxicity in Peruvian Pa-tients. Int J Mol Sci 2022; 23(19):11028. doi:10.3390/ijms231911028,PMID:36232322.

[8] Dakh KS, Patekar RR, Choudhary HB, Momin AZ, Undale VR, Mahadik P, et al. Herbal approach for tuberculosis management: A system-atic review. World J Adv Res Rev 2022; 14:637-647. doi:10.30574/wjarr.2022.14.2.0426.

[9] Gautam S, Qureshi KA, Jameel Pasha SB, Dhanasekaran S, Aspatwar A, Parkkila S, et al. Medicinal Plants as Therapeutic Alternatives to Combat Mycobacterium tuberculosis: A Comprehensive Review. An-tibiotics (Basel) 2023; 12(3):541. doi:10.3390/antibiotics12030541,PMID:36978408.

[10] Shih TY, Pai CY, Yang P, Chang WL, Wang NC, Hu OY. A novel mech-anism underlies the hepatotoxicity of pyrazinamide. Antimicrob Agents Chemother 2013; 57(4):1685-1690. doi:10.1128/AAC.01866-12,PMID:23357778.

[11] Shah PR, Sajan C, Mistry M. Antituberculosis drug induced hepatitis: a case report. Indian J Pharm Pract 2022; 15(2):144-147. doi:10.5530/ijopp.15.2.25.

[12] Singh A, Prasad R, Balasubramanian V, Gupta N, Gupta P. Preva-lence of adverse drug reaction with first line drug among patients treated for pulmonary tuberculosis. Clin Epidemiol Global Health 2015; 3(1):S80-S90. doi:10.1016/j.cegh.2015.10.005.

[13] Jiménez-Arellanes MA, Gutiérrez-Rebolledo GA, Meckes-Fischer M, León-Díaz R. Medical plant extracts and natural compounds with a hepatoprotective effect against damage caused by antitubercu-lar drugs: A review. Asian Pac J Trop Med 2016; 9(12):1141-1149. doi:10.1016/j.apjtm.2016.10.010,PMID:27955741.

[14] Edwards BD, Mah H, Sabur NF, Brode SK. Hepatotoxicity and tubercu-losis treatment outcomes in chronic liver disease. J Assoc Med Micro-biol Infect Dis Can 2023; 8(1):64-74. doi:10.3138/jammi-2022-0029,PMID:37008589.

[15] Chakaya J, Khan M, Ntoumi F, Aklillu E, Fatima R, Mwaba P, et al. Global Tuberculosis Report 2020 - Reflections on the Global TB bur-den, treatment and prevention efforts. Int J Infect Dis 2021; 113(Sup-pl 1):S7-S12. doi:10.1016/j.ijid.2021.02.107,PMID:33716195.

[16] Zhuang X, Li L, Liu T, Zhang R, Yang P, Wang X, et al. Mechanisms of isoniazid and rifampicin-induced liver injury and the effects of natural medicinal ingredients: A review. Front Pharmacol 2022;13:1037814. doi:10.3389/fphar.2022.1037814,PMID:36299895.

[17] Zhang G, Chen L, Wen Y, Rao Z, Wei Y, Wu X. Pyridoxal isonicotinoyl hydrazone inhibition of FXR is involved in the pathogenesis of isoni-azid-induced liver injury. Toxicol Appl Pharmacol 2020;402:115134. doi:10.1016/j.taap.2020.115134,PMID:32673658.

[18] Devarbhavi H, Singh R, Patil M, Sheth K, Adarsh CK, Balaraju G. Outcome and determinants of mortality in 269 patients with com-bination anti-tuberculosis drug-induced liver injury. J Gastroen-terol Hepatol 2013; 28(1):161-167. doi:10.1111/j.1440-1746.2012.07279.x, PMID:23020522.

[19] Naji KM, Al-Khatib BY, Al-Haj NS, D’souza MR. Hepatoprotective ac-tivity of melittin on isoniazid- and rifampicin-induced liver injuries in male albino rats. BMC Pharmacol Toxicol 2021; 22(1):39. doi:10.1186/s40360-021-00507-9,PMID:34217369.

[20] Soedarsono MS, Prayuni K, Yuliwulandari R. The risk factors for drug-induced hepatitis in pulmonary tuberculosis and tuberculosis in spe-cial situation in dr. Soetomo. IJTID 2018; 7(3):73-79. doi:10.20473/ijtid.v7i3.8689.

[21] Lei S, Gu R, Ma X. Clinical perspectives of isoniazid-induced liver in-jury. Liver Res 2021; 5:45-52. doi:10.1016/j.livres.2021.02.001.

[22] Adhvaryu MR, Reddy N, Vakharia BC. Prevention of hepatotoxicity due to anti tuberculosis treatment: a novel integrative approach. World J Gastroenterol 2008; 14(30):4753-4762. doi:10.3748/wjg.14.4753,PMID:18720535.

[23] Ramappa V, Aithal GP. Hepatotoxicity Related to Anti-tubercu-losis Drugs: Mechanisms and Management. J Clin Exp Hepatol 2013; 3(1):37-49. doi:10.1016/j.jceh.2012.12.001,PMID:25755470.

[24] Shen T, Liu Y, Shang J, Xie Q, Li J, Yan M, et al. Incidence and Etiol-ogy of Drug-Induced Liver Injury in Mainland China. Gastroenterol-ogy 2019; 156(8):2230-2241.e11. doi:10.1053/j.gastro.2019.02.002,PMID:30742832.

[25] Hong M, Li S, Tan HY, Wang N, Tsao SW, Feng Y. Current Status of Herbal Medicines in Chronic Liver Disease Therapy: The Biological Effects, Mo-lecular Targets and Future Prospects. Int J Mol Sci 2015; 16(12):28705-45. doi:10.3390/ijms161226126,PMID:26633388.

[26] Getachew S, Medhin G, Asres A, Abebe G, Ameni G. Traditional medicinal plants used in the treatment of tuberculosis in Ethiopia: A systematic review. Heliyon 2022; 8(5):e09478. doi:10.1016/j.heli-yon.2022.e09478,PMID:35647341.

[27] Mpeirwe M, Taremwa IM, Orikiriza P, Ogwang PE, Ssesazi D, Bazira J. Anti-mycobacterial activity of medicinal plant extracts used in the treatment of tuberculosis by traditional medicine practition-ers in Uganda. Pharmacol Pharm 2023; 14:33-42. doi:10.4236/pp.2023.142003.

[28] Obakiro SB, Kiprop A, Kowino I, Kigondu E, Odero MP, Omara T, et al. Ethnobotany, ethnopharmacology, and phytochemistry of traditional medicinal plants used in the management of symptoms of tubercu-losis in East Africa: a systematic review. Trop Med Health 2020; 48:68. doi:10.1186/s41182-020-00256-1,PMID:32818019.

[29] Sarangi A, Das BS, Patnaik G, Sarkar S, Debnath M, Mohan M, et al. Potent anti-mycobacterial and immunomodulatory activity of some bioactive molecules of Indian ethnomedicinal plants that have the potential to enter in TB management. J Appl Microbiol 2021; 131(4):1578-1599. doi:10.1111/jam.15088,PMID:33772980.

[30] Xu Y, Liang B, Kong C, Sun Z. Traditional Medicinal Plants as a Source of Antituberculosis Drugs: A System Review. Biomed Res Int 2021; 2021:9910365. doi:10.1155/2021/9910365,PMID:34541000.

[31] Himaja N. Comparative study of hepatoprotective activity of Acan-thospermum hispidum plant extract and herbal Niosomal suspen-sion against anti-tubercular drug induced hepatotoxicity in rats. Asian J Pharm Clin Res 2015; 8(5):256-259.

[32] Etienne EK, Landry KS, Geneviève IA, Aminata A. Gisèle KN. Hepatoprotective effects of methanol extract of Alchornea cordi-folia leaves against anti-tubercular drugs induced hepatotoxicity in rats. Afri J Pharm Pharmacol 2017; 11(39):501-508. doi:10.5897/AJPP2017.4841.

[33] Ilyas N, Sadiq M, Jehanger A. Hepatoprotective effect of garlic (Allium sativum) and milk thistle (silymarin) in isoniazid induced hepatotox-icity in rats. Biomedical 2011; 27:166-170.

[34] Bello B, Wudil AM. Protective effect of Allium sativum against liver injury induced by antitubercular drug in rats. Br J Pharmacol Toxicol 2012; 3(2):89-92.

[35] Pal R, Vaiphei K, Sikander A, Singh K, Rana SV. Effect of garlic on iso-niazid and rifampicin-induced hepatic injury in rats. World J Gastro-enterol 2006; 12(4):636-639. doi:10.3748/wjg.v12.i4.636,PMID:16489682.

[36] Mawarti H, Rajin M, Asumta Z. The Effects of Aloe Vera on TNF-a Levels, the Percentage of Nk Cells and Th 17 Cells in Rat That Re-ceived Izoniazid and Rifampycin. Med Arch 2017; 71(5):308-311. doi:10.5455/medarh,PMID:29284895.

[37] Ishtiaq S, Afridi MSK. Amelioration of isoniazid and rifampicin-in-duced liver toxicity by Amaranthus subsp. silvestris in rat. Bangladesh J Pharmacol 2017; 12:354-358. doi:10.3329/bjp.v12i3.32985.

[38] Usmani A, Mujahid M, Khushtar M, Siddiqui HH, Rahman MA. Hepatoprotective effect of Anacyclus pyrethrum Linn. against antitu-bercular drug-induced hepatotoxicity in SD rats. J Complement Integr Med 2016; 13(3):295-300. doi:10.1515/jcim-2016-0001,PMID:27101559.

[39] Thattakudian Sheik Uduman MS, Sundarapandian R, Muthumanik-kam A, Kalimuthu G, Parameswari SA, Vasanthi Srinivas TR, et al. Protective effect of methanolic extract of Annona squamosa Linn in isoniazid-rifampicin induced hepatotoxicity in rats. Pak J Pharm Sci 2011; 24(2):129-34. PMID:21454160.

[40] Mitra P, Ghosh T, Mitra PK. Seasonal variation in hepatoprotective activity of Titeypti (Artemisia vulgaris) leaves on antitubercular drugs induced hepatotoxicity in rats. SMU Med J 2016; 3(1):763-774.

[41] Palanisamy N, Manian S. Protective effects of Asparagus rac-emosus on oxidative damage in isoniazid-induced hepatotoxic rats: an in vivo study. Toxicol Ind Health 2012; 28(3):238-244. doi:10.1177/0748233711410911,PMID:21724661.

[42] Lina SMM, Ashab I, Ahmed I, Shahriar M. Hepatoprotective activity of Asteracantha longifolia (Nees) extract against anti-tuberculosis drugs induced hepatic damage in Sprangue-Dawley rats. Pharma-cologyOnline 2012; 3:13-19.

[43] Kale BP kothekar MA, Tayade HP, Jaju JB, Mateenuddin M. Effect of aqueous extract of Azadirachta indica leaves on hepatotoxicity in-duced by antitubercular drugs in rats. Indian J Pharm 2003; 35:177-180.

[44] Evan Prince S, Udhaya LB, Sunitha PS, Arumugam G. Reparation of Isoniazid and Rifampicin Combinatorial Therapy-Induced Hepatotox-ic Effects by Bacopa monnieri. Pharmacology 2016; 98(1-2):29-34. doi:10.1159/000444856,PMID:27007136.

[45] Muthulingam M. Antihepatotoxic effects of Boerhaavia diffusa L. on antituberculosis drug, rifampicin induced liver injury in rats. J Phar-macol Toxicol 2008; 3(2):75-83. doi:10.3923/jpt.2008.75.83.

[46] Ravi V, Patel SS, Verma NK, Dutta D, Saleem TSM. Hepatoprotec-tive activity of Bombax ceiba Linn against isoniazid and rifampic-in-induced toxicity in experimental rats. Int J Appl Res Natur Prod 2010; 3(3):19-26.

[47] Jaydeokar AV, Bandawane DD, Bibave KH, Patil TV. Hepatoprotective potential of Cassia auriculata roots on ethanol and antitubercular drug-induced hepatotoxicity in experimental models. Pharm Biol 2014; 52(3):344-355. doi:10.3109/13880209.2013837075,PMID:24472085.

[48] Jehangir A, Nagi AH, Shahzad M, Zia A. The hepato-protective effect of Cassia fistula (Amaltas) leaves in isoniazid and rifampicin induced hepatotoxicity in rodents. Biomedica 2010; 26:25-29.

[49] Kumar V, Sharma A, Machawal L, Nagarajan K, Siddiqui SA. Effect of Centella asiatica against anti-tuberculosis hepatotoxicity: involve-ment of mitochondria and oxidative stress. JPHYTO 2014; 3(5):310-315. doi:10.31254/phyto.2014.3502.

[50] Balakrishnan 1 S, Khurana BS, Singh A, Kaliappan I, Dubey GP. Hepatoprotective effect of hydroalcoholic extract of Cissampe-los pareira against rifampicin and isoniazid induced hepatotoxic-ity. Continental J. Pharm Sci 2012; 6(1):30-35. doi:10.5707/cjpharm.sci.2012.6.1.30.35.

[51] Kosasih E, Chiuman L, Lister INE, Fachrial E. Hepatoprotective ef-fect of Citrus sinensis peel extract against isoniazid and rifampicin-induced liver injury in wistar rats. Trad Med J 2019; 24(3):197-203. doi:10.22146/mot.45762.

[52] Pérez-González MZ, Macías-Rubalcava ML, Hernández-Ortega S, Sior-dia-Reyes AG, Jiménez-Arellanes MA. Additional compounds and the therapeutic potential of Cnidoscolus chayamansa (McVaugh) against hepatotoxicity induced by antitubercular drugs. Biomed Pharmacoth-er 2019;117:109140. doi:10.1016/j.biopha.2019.109140,PMID:31387195.

[53] Pillai KK, Chidambaranathan N, Halith MM, Jayaprakash S, Narayanan N. Hepatoprotective activity of Cnidoscolus chayamansa against ri-fampicin and isoniazid induced toxicity in Wistar rats. Res J Pharm Biol Chem Sci 2012; 3(2):577-585.

[54] Wali AF, Pillai JR, Al Dhaheri Y, Rehman MU, Shoaib A, Sarheed O, et al. Crocus sativus L. Extract Containing Polyphenols Modulates Oxidative Stress and Inflammatory Response against Anti-Tuber-culosis Drugs-Induced Liver Injury. Plants (Basel) 2020; 9(2):167. doi:10.3390/plants9020167,PMID:32019201.

[55] Gopalakrishnan SB, Kalaiarasi T. Hepatoprotective activity studies of Cucumis trigonus Roxb. Against rifampicin-isoniazid-induced toxicity in rats. Eur J Pharm Med Res 2015; 2(6):141-146.

[56] Adhvaryu MR, Reddy N, Parabia MH. Effects of four Indian medici-nal herbs on Isoniazid-, Rifampicin- and Pyrazinamide-induced he-patic injury and immunosuppression in guinea pigs. World J Gas-troenterol 2007; 13(23):3199-3205. doi:10.3748/wjg.v13.i23.3199,PMID:17589898.

[57] Abd El-Kader EM, Hassan WA, Abd Al-Haleem EN, Amany KA, Raslan YA. Curcuma longa and Nigel sativa modulate the hepatotoxic effect of anti-tuberculosis drugs and acetaminophenin rats. IOSR J Pharm Biol Sci 2018; 13(3):65-78. doi:10.9790/3008-1303016578.

[58] Sambrekar SN, Patil PA, Kangralkar VA. Protective effect of Embelia tsjeriam-cottam fruit extracts on isoniazid induced hepatotoxicity in wistar rats. Int J Pharm Sci Rev Res 2010; 4(1):136-139.

[59] Tasduq SA, Kaisar P, Gupta DK, Kapahi BK, Maheshwari HS, Jyotsna S, et al. Protective effect of a 50% hydroalcoholic fruit extract of Emblica officinalis against anti-tuberculosis drugs induced liver toxicity. Phytother Res 2005; 19(3):193-197. doi:10.1002/ptr.1631,PMID:15934014.

[60] Mujahid M, Hussain T, Siddiqui HH, Hussain A. Evaluation of hepato-protective potential of Erythrina indica leaves against antituber-cular drugs induced hepatotoxicity in experimental rats. J Ayur-veda Integr Med 2017; 8(1):7-12. doi:10.1016/j.jaim.2016.10.005,PMID:27916487.

[61] Lall N, Kumar V, Meyer D, Gasa N, Hamilton C, Matsabisa M, et al. In vitro and In vivo antimycobacterial, hepatoprotective and immu-nomodulatory activity of Euclea natalensis and its mode of action. J Ethnopharmacol 2016; 194:740-748. doi:10.1016/j.jep.2016.10.060,PMID:27773800.

[62] Parameswari SA, Chetty CM, Chandrasekhar KB. Hepatoprotective activity of Ficus religiosa leaves against isoniazid+rifampicin and par-acetamol induced hepatotoxicity. Pharmacognosy Res 2013; 5(4):271-276. doi:10.4103/0974-8490.118828,PMID:24174821.

[63] Prabakan M, Anandan R, Devaki T. Protective effect of Hemides-mus indicus against rifampicin and isoniazid-induced hepatotox-icity in rats. Fitoterapia 2000;71(1):55-59. doi:10.1016/s0367-326x(99)00120-3, PMID:11449471.

[64] Samuel AJ, Mohan S, Chellappan DK, Kalusalingam A, Ariamuthu S. Hibiscus vitifolius ( Linn.) root extracts shows potent protective action against anti-tubercular drug induced hepatotoxicity. J Ethnopharma-col 2012; 141(1):396-402. doi:10.1016/j.jep.2012.02.051,PMID:22421378.

[65] Nwidu LL, Teme RE. Hot aqueous leaf extract of Lasianthera africana (Icacinaceae) attenuates rifampicin-isoniazid-induced hepatotoxici-ty. J Integr Med 2018; 16(4):263-272. doi:10.1016/joim.2018.05.001,PMID:29776838.

[66] Darvin SS, Esakkimuthu S, Toppo E, Balakrishna K, Paulraj MG, Pandi-kumar P, et al. Hepatoprotective effect of lawsone on rifampicin-iso-niazid induced hepatotoxicity in in vitro and in vivo models. Environ Toxicol Pharmacol 2018; 61:87-94. doi:10.1016/j.etap.2018.05.006,PMID:29859372.

[67] Bais B, Saiju P. Ameliorative effect of Leucas cephalotes extract on isoniazid and rifampicin induced hepatotoxicity. Asian Pac J Trop Bi-omed 2014; 4(Suppl 2):S633-S638. doi:10.12980/APJTB.4.2014APJTB-2014-0236.

[68] Jadhav VB, Thakare VN, Suralkar AA, Deshpande AD, Naik SR. Hepato-protective activity of Luffa acutangula against CCl4 and rifampicin induced liver toxicity in rats: a biochemical and histopathological evaluation. Indian J Exp Biol 2010; 48(8):822-829. PMID:21341541.

[69] Shabbir M, Afsar T, Razak S, Almajwal A, Khan MR. Phytochemical analysis and Evaluation of hepatoprotective effect of Maytenus royleanus leaves extract against anti-tuberculosis drug induced liver injury in mice. Lipids Health Dis 2020; 19(1):46. doi:10.1186/s12944-020-01231-9,PMID:32178678.

[70] Ali ZY. Biochemical evaluation of some natural products against toxic-ity induced by anti-tubercular drugs in rats. N Y Sci J 2012; 5(10):69-80.

[71] Dong Y, Huang J, Lin X, Zhang S, Jiao Y, Liang T, et al. Hepatoprotective effects of Yulangsan polysaccharide against isoniazid and rifampicin-induced liver injury in mice. J Ethnopharmacol 2014; 152(1):201-206. doi:10.1016/j.jep.2014.01.001,PMID:24412379.

[72] Jyothi B, Mohanalakshmi S, Anitha K. Protective effect of Mirabilis jalapa leaves on anti-tubercular drugs induced hepatotoxicity. Asian J Pharm Clin Res 2013; 6(30):221-224.

[73] Ullah I, Khan JA, Adhikari A, Shahid M. Hepatoprotective effect of Monotheca buxifolia fruit against antitubercular drugs-induced hepatotoxicity in rats. Bangladesh J Pharmacol 2016; 11:248-56. doi:10.3329/bjp.v11i1.25289.

[74] Pari L, Kumar NA. Hepatoprotective activity of Moringa oleifera on antitubercular drug-induced liver damage in rats. J Med Food 2002; 5(3):171-177. doi:10.1089/10966200260398206,PMID:12495589.

[75] Obogwu MB, Akindele AJ, Adeyemi OO. Hepatoprotective and in vivo antioxidant activities of the hydroethanolic leaf extract of Mucuna pruriens (Fabaceae) in antitubercular drugs and alcohol models. Chin J Nat Med 2014;12(4):273-283. doi:10.1016/S1875-5364(14)60054-6, PMID:24863352.

[76] Jaswal A, Sharma M, Raghuvanshi S, Sharma S, Reshi MS, Uthra C, et al. Therapeutic Efficacy of Nigella Sativa Linn. against Antituber-culosis Drug-Induced Hepatic Injury in Wistar Rats. J Environ Pathol Toxicol Oncol 2016; 35(1):59-71. doi:10.1615/JEnvironPatholToxico-lOncol.2016013789,PMID:27279584.

[77] Hassan AS, Ahmed JH, Al-Haroon SS. A study of the effect of Nigella sativa (Black seeds) in isoniazid (INH)-induced hepatotoxicity in rab-bits. Indian J Pharmacol 2012; 44(6):678-682. doi:10.4103/0253-7613.103239,PMID:23248393.

[78] Nasiruddin N, Khan IA, Arif SH. Therapeutic effect of Nymphaea alba linn. flowers against isoniazid-induced hepatotoxicity: an experimen-tal study. Asisn J Pharm Clin Res 2018; 11(5):333-336. doi:10.22159/ajpcr.2018.v11i5.22830.

[79] Mishra G, Chandra HK, Sahu N, Nirala SK, Bhadauria M. Forssk.) Chiov. Ameliora-tive effect of Pergularia daemia ( leaves extract against anti-tuberculosis drugs induced liver injury in rats. Asian Pacific J Trop Med 2018; 11(9):518-525. doi:10.4103/1995-7645.242310.

[80] Koppal A, Praveen SE, Shanbhag T, Kushal A, Mathew D, Shenoy S, et al. Evaluation of effect of ethanolic extract of Phyllanthus debilis on antitubercular drugs induced hepatotoxicity in wistar rats. World J Pharm Res 2014; 3(4):1997-2003.

[81] Jeyakumar R, Rajesh R, Rajaprabhu D, Ganesan B, Buddhan S, Anan-dan R. Hepatoprotective effect of Picrorrhiza kurroa on antioxidant defense system in antitubercular drugs induced hepatotoxicity in rats. Afr J Biotechnol 2009; 8(7):1314-1315.

[82] Anbarasu C, Rajkapoor B, Kalpana J. Protective effect of Pisonia acu-leate on rifampicin and isoniazid induced hepatotoxicity in rats. Int J Phytomed 2011; 3:75-83. doi:10.5455/jeim.040511.or.008.

[83] Yogeeta S, Ragavender HRB, Devaki T. Antihepatotoxic effect of Pu-nica granatum acetone extract against isoniazid and rifampicin-in-duced hepatotoxicity. Pharm Biol 2007; 45(8):631-637. doi:10.1080/13880200701538963.

[84] Khan SW, Tahir M, Lone KP, Munir B, Latif W. Protective effect of Saccharum officinarum L. (sugar cane) juice on isoniazid induced hepatotoxicity in male albino mice. J Ayub Med Coll Abbottabad 2015; 27(2):346-350.

[85] Wang J, Luo W, Li B, Lv J, Ke X, Ge D, et al. Sagittaria sagittifolia poly-saccharide protects against isoniazid- and rifampicin-induced he-patic injury via activation of nuclear factor E2-related factor 2 sign-aling in mice. J Ethnopharmacol 2018; 227:237-245. doi:10.1016/j.jep.2018.09.002, PMID:30194055.

[86] Hussain T, Gupta RK, K S, Khan MS, Hussain MD, Arif MD, et al. Evalu-ation of antihepatotoxic potential of Solanum xanthocarpum fruit ex-tract against antitubercular drugs induced hepatopathy in experimen-tal rodents. Asian Pac J Trop Biomed 2012;2(6):454-460. doi:10.1016/S2221-1691(12)60075-6, PMID:23569949.

[87] Martin SJ, Baskaran UL, Vedi M, Sabina EP.Attenuation of anti-tuber-culosis therapy induced hepatotoxicity by Spirulina fusiformis, a candi-date food supplement. Toxicol Mech Methods 2014; 24(8):584-592. d oi:10.3109/15376516.2014.956910, PMID:25137345.

[88] Jatav SK, Kulshrestha A, Zacharia A, Singh N, Tejovathi G, Bisen PS, et al. Spirulina maxima Protects Liver From Isoniazid and Rifampicin Drug Toxicity. J Evid Based Complementary Altern Med 2014; 19(3):189-194. doi:10.1177/2156587214530720,PMID:24742608.

[89] Amir M, Khan MA, Ahmad S, Akhtar M, Mujeeb M, Ahmad A, et al. Ameliorating effects of Tamarindus indica fruit extract on anti-tuber-cular drugs induced liver toxicity in rats. Nat Prod Res 2016; 30(6):715-719. doi:10.1080/14786419.2015.1039001,PMID:25978515.

[90] Meena SZ, Rahman MA, Bagga P, Mujahid M. Hepatoprotective activity of Tamarindus indica Linn stem bark ethanolic extract against hepatic damage induced by co-administration of antitubercular drugs isoniazid and rifampicin in Sprague Dawley rats. J Basic Clin Physiol Pharmacol 2018; 30(1):131-137. doi:10.1515/jbcpp-2017-0173,PMID:30179850.

[91] Urfi MK, Mujahid M, Rahman MA, Rahman MA. The Role of Tamarix gallica Leaves Extract in Liver Injury Induced by Rifampicin Plus Isonia-zid in Sprague Dawley Rats. J Diet Suppl 2018; 15(1):24-33. doi:10.1080/19390211.2017.1310783,PMID:28459346.

[92] Nwidu LL, Oboma YI. Telfairia occidentalis (Cucurbitaceae) pulp ex-tract mitigates rifampicin-isoniazid-induced hepatotoxicity in an in vivo rat model of oxidative stress. J Integr Med 2019; 17(1):46-56. doi:10.1016/j.joim.2018.11.008,PMID:30555014.

[93] Tasduq SA, Singh K, Satti NK, Gupta DK, Suri KA, Johri RK. Terminalia chebula (fruit) prevents liver toxicity caused by sub-chronic adminis-tration of rifampicin, isoniazid and pyrazinamide in combination. Hum Exp Toxicol 2006; 25(3):111-118. doi:10.1191/0960327106ht601oa,PMID:16634329.

[94] Hussain T, Subaiea GM, Firdous H. Hepatoprotective Evaluation of Trapa natans against Drug-induced Hepatotoxicity of Antitubercular Agents in Rats. Pharmacogn Mag 2018; 14(54):180-185. doi:10.4103/pm.pm_237_17,PMID:29720828.

[95] Tandon VR, Khajuria V, Kapoor B, Kour D, Gupta S. Hepatoprotec-tive activity of Vitex negundo leaf extract against anti-tubercular drugs induced hepatotoxicity. Fitoterapia 2008; 79(7-8):533-538. doi:10.1016/j.fitote.2008.05.005,PMID:18621114.

[96] Rao ChV, Rawat AK, Singh AP, Singh A, Verma N. Hepatoprotective po-tential of ethanolic extract of Ziziphus oenoplia (L.) Mill roots against antitubercular drugs induced hepatotoxicity in experimental mod-els. Asian Pac J Trop Med 2012;5(4):283-288. doi:10.1016/S1995-7645(12)60040-6, PMID:22449519.

[97] Altemimi A, Lakhssassi N, Baharlouei A, Watson DG, Lightfoot DA. Phy-tochemicals: Extraction, Isolation, and Identification of Bioactive Com-pounds from Plant Extracts. Plants (Basel) 2017; 6(4):42. doi:10.3390/plants6040042,PMID:28937585.

[98] Panyod S, Wu WK, Ho CT, Lu KH, Liu CT, Chu YL, et al. Diet Supple-mentation with Allicin Protects against Alcoholic Fatty Liver Disease in Mice by Improving Anti-inflammation and Antioxidative Functions. J Agric Food Chem 2016; 64(38):7104-13. doi:10.1021/acs.jafc.6b02763,PMID:27584700.

[99] Liu CM, Ma JQ, Xie WR, Liu SS, Feng ZJ, Zheng GH, et al. Quercetin pro-tects mouse liver against nickel-induced DNA methylation and inflam-mation associated with the Nrf2/HO-1 and p38/STAT1/NF-κB pathway. Food Chem Toxicol 2015; 82:19-26. doi:10.1016/j.fct.2015.05.001,PMID:25957741.

[100] Nam JS, Sharma AR, Nguyen LT, Chakraborty C, Sharma G, Lee SS. Application of Bioactive Quercetin in Oncotherapy: From Nutrition to Nanomedicine. Molecules 2016; 21(1):E108. doi:10.3390/mole-cules21010108,PMID:26797598.

[101] Sumathi T, Nongbri A. Hepatoprotective effect of Bacoside-A, a major constituent of Bacopa monniera Linn. Phytomedicine 2008; 15(10):901-905. doi:10.1016/j.phymed.2007.11.020,PMID:18222663.

[102] Zhang J, Xu L, Zhang L, Ying Z, Su W, Wang T. Curcumin attenuates D-galactosamine/lipopolysaccharide-induced liver injury and mitochon-drial dysfunction in mice. J Nutr 2014; 144(8):1211-1218. doi:10.3945/jn.114.193573,PMID:24899159.

[103] Jakubczyk K, Drużga A, Katarzyna J, Skonieczna-Żydecka K. Antioxidant Potential of Curcumin-A Meta-Analysis of Randomized Clinical Tri-als. Antioxidants (Basel) 2020; 9(11):92. doi:10.3390/antiox9111092,PMID:33172016.

[104] Javed S, Shoaib A, Mahmood Z, Ishtiaq S. Hepatoprotective effect of methanolic extract of Monotheca buxifolia against isoniazid and ri-fampicin induced hepatotoxicity. Asian J Agric Biol 2021;4:202102074. doi:10.35495/ajab.2021.02.074.

[105] Malviya N, Jain S, Jain A, Jain S, Gurjar R. Evaluation of in vitro anti-oxidant potential of aqueous extract of Trapa natans L. fruits. Acta Pol Pharm 2010; 67(4):391-396. PMID:20635535.

[106] Qader GI, Aziz R, Ahmed Z, Abdullah Z, Hussain SA. Protective effects of quercetin against isoniazid and rifampicin induced hepatotoxicity in rats. Am J Pharmacol Sci 2014; 2(3):56-60. doi:10.12691/ajps-2-3-3.

[107] Chen Y T, Wang D W, Zhang J B, Wang W, Wang JT, Sheng Y L, et al. Involvement of the ROS/Caspase-3 signaling pathway in isoniazid-in-duced apoptosis in L-02 cells and the protective effect of quercetin. Carcinog Teratogenesis Mutagen 2019; 31(1):53-57+68. doi:10.3969/j.issn.1004-616x.2019.01.010.

[108] Chen Y T, Chen DS, He SB, Yi YF, Shen H, Lin JB, et al. The role of ROS/JNK pathway in the inhibition of isoniazid-induced hepatocyte apopto-sis by quercetin. J Huzhou Univ 2021; 43(8):59-64.

[109] Chen YT, Chen DY, Xie JL, Gao XR, Lu JF. Role of the Nrf2/ARE sign-aling pathway on quercetin-inhibition of INH-induced mitochondrial oxidative damage in hepatocytes. Carcinog Teratogenesis Mutagen 2021; 33(3):208-212+217. doi:10.3969/j.issn.1004-616x.2021.03.009.

[110] Zhang Y, Zhang W, Tao L, Zhai J, Gao H, Song Y, et al. Quercetin pro-tected against isoniazide-induced HepG2 cell apoptosis by activating the SIRT1/ERK pathway. J Biochem Mol Toxicol 2019; 33(9):e22369. doi:10.1002/jbt.22369,PMID:31332904.

[111] Zhang L, Lu Y. Research progress on the mechanism of first-line antitu-berculosis drugs-induced liver injury. Clin Medicat J 2020; 18(7):21-25. doi:10.3969/j.issn.1672-3384.2020.07.006.

[112] Wang J, Lyu JP, Ke XH, Li B, Yu HC, Han Y, et al. Effects of Sagitta-ria sagittifolin polysaccharide on CYP2E1 and CYP3A4 in INH/RFP-induced hepatotoxicity in HepG2 cells. Chin Arch Trad Chin Med 2018; 36(9):2230-2233. doi:10.13193/j.issn.1673-7717.2018.09.046.

[113] Liu HS, Wang J, Zhang YY, Zhang X, Liao Y. In vivo and in vitro experi-mental study on the protective effect of Nrf2 activated by Sagittaria Sagittifolia polysaccharides on liver injury caused by isoniazid and ri-fampicin in combination. China J Trad Med Pharm 2022; 37(2):1112-1117.

[114] Wang R, Han L, Zhao GL. Protective effect and mechanism of Prunella vulgaris sulfate polysaccharide on liver injury induced by isoniazid mice. Chin J Clin Gastroenterol 2021; 33(4):242-245. doi:10.3870/lcxh.j.issn.1005-541X.2021.04.04.

[115] Kumar S, Pandey AK. Chemistry and biological activities of fla-vonoids: an overview. ScientificWorldJournal 2013; 2013:162750. doi:10.1155/2013/162750,PMID:24470791.

[116] Xi BT, Zhu ML, Gao Y, Zhang KF. The protective effect and mechanism of total flavonoids extracted from Polygonum perfoliatum L. in anti-tu-berculosis drugs-induced liver injury in mice. Pharmacol. Clin Chin Ma-teria Medica 2017; 33(5):51-54. doi:10.13412/j.cnki.zyyl.2017.05.014.

[117] Wang XX, An JH, Wang ZL. Protective effect of total flavonoids extract-ed from Polygonum perfoliatum L. on the liver injury caused by anti-tuberculosis drugs in mice. Chin J Clin Pharmacol 2021; 37(6):713-717. doi:10.13699/j.cnki.1001-6821.2021.06.017.

[118] He L, Guo Y, Deng Y, Li C, Zuo C, Peng W. Involvement of protoporphyrin IX accumulation in the pathogenesis of isoniazid/rifampicin-induced liver injury: the prevention of curcumin. Xenobiotica 2017; 47(2):154-163. doi:10.3109/00498254.2016.1160159,PMID:28118809.