Effects of Chrysin Against Isoniazid-Induced Lung Injury in Rats

Year 2020, Volume: 13 Issue: 2, 161 - 171, 30.06.2020

Sefa Küçükler , Selçuk Özdemir , Selim Çomaklı , Fatih Kandemir

https://doi.org/10.30607/kvj.709842

Cited By: 1

Abstract

The aim of the study was to investigate the effects of chrysin (CH), one of the natural flavonoids, against isoniazid lung damage caused by isoniazid (INH), which was widely used in the treatment of tuberculosis. Male Sprague-Dawley rats were randomly divided into five groups: a control group, INH-treated group, CH alone treated group 50 mg / kg, INH + CH 25 mg / kg treated group, and INH+ CH 50 mg / kg treated group. It was determined that INH caused oxidative damage by decreasing antioxidant enzyme activities such as glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) and increasing lipid peroxidation (LPO). In addition, it was found that the administration of CH to INH-treated rats increased GSH level and antioxidant enzyme activities, and decreased lipid peroxidation. It was observed that the nuclear factor erythroid 2 related factor 2 (Nrf-2) and oxygenase-1 (HO-1) expression levels were up-regulated in the INH-treated group, and the expression of NF-κB increased in the INH-treated group in the immunohistochemical examination, and the CH administration, on the other hand, decreased the levels of these markers. Taken together, these results suggested that CH had beneficial effects in INH-induced lung toxicity by maintaining the oxidant-antioxidant balance and decreasing NF-κB, Nrf-2, and HO-1 expressions.

Keywords

Chrysin, Isoniazid, Lung, Oxidative Stress

Ratlarda İzoniazid Kaynaklı Akciğer Hasarına Karşı Krisinin Etkileri

Abstract

Bu çalışmanın amacı; tüberküloz tedavisinde yaygın olarak kullanılan izoniazid (İZN) kaynaklı akciğer hasarına karşı doğal flavonoidlerden olan krisin (KRS)’in etkilerinin araştırılmasıdır. Çalışmada Spraque Dawley cinsi 35 adet erkek rat rastgele 5 gruba ayrıldı: Kontrol grubu, İZN uygulanan grup, KRS 50 mg/kg uygulanan grup, İZN+ KRS 25 mg/kg uygulanan grup ve İZN+ KRS 50 mg/kg uygulanan grup. İZN’nin glutatyon peroksidaz (GPx), süperoksit dismutaz (SOD) ve katalaz (KAT) gibi antioksidan enzim aktivitelerini ve glutatyon (GSH) düzeylerini azaltıp, lipid peroksidasyonunu (LPO) artırarak oksidatif hasara neden olduğu belirlendi. Ayrıca İZN ile kombine uygulanan KRS uygulamasının GSH seviyesini ve antioksidan enzim aktivitelerini artırdığı, lipid peroksidasyonunu ise azalttığı ettiği tespit edildi. Çalışmada incelenen nükleer faktör eritroid 2 ile ilişkili faktör 2 (Nrf-2) ve hem oksijenaz-1 (HO-1) seviyelerinin İZN grubunda gen ekspresyonu düzeyinde, nükleer faktör kappa B (NF-κB) ekspresyonunu ise immunhistokimyasal incelemede arttığı tespit edilmiş, buna karşın KRS uygulamasının bu belirteçlerin düzeylerinde azalmaya neden olduğu gözlenmiştir. Birlikte ele alındığında, bu sonuçlar KRS'in oksidan-antioksidan dengesini koruyarak ve NF-κB, Nrf-2 ve HO-1 ekspresyonlarını azaltarak İZN’nin neden olduğu akciğer toksisitesinde faydalı etkilere sahip olduğunu düşündürmektedir.

Keywords

Akciğer, İzoniazid, Krisin, Oksidatif Stres

References

• Abass MA, Elkhateeb SA, El-baset SAA, Kattaia AA, Mohamed EM, Atteia HH. Lycopene ameliorates atrazine-induced oxidative damage in adrenal cortex of male rats by activation of the Nrf2/HO-1 pathway Environ Sci Pollut. 2016; 23:15262-15274.
• Aebi H. Catalase. In: Methods of enzymatic analysis. Elsevier, pp 1974; 673-684.
• Agca CA, Tuzcu M, Hayirli A, Sahin K. Taurine ameliorates neuropathy via regulating NF-κB and Nrf2/HO-1 signaling cascades in diabetic rats Food Chem Toxicol. 2014; 71:116-121.
• Ahadpour M, Eskandari MR, Mashayekhi V, Haj Mohammad Ebrahim Tehrani K, Jafarian I, Naserzadeh P, Hosseini M-J. Mitochondrial oxidative stress and dysfunction induced by isoniazid: study on isolated rat liver and brain mitochondria Drug Chem Toxicol. 2016; 39:224-232.
• Aksu E, Kandemir F, Özkaraca M, Ömür A, Küçükler S, Çomaklı S. Rutin ameliorates cisplatin‐induced reproductive damage via suppression of oxidative stress and apoptosis in adult male rats Andrologia 2017; 49:e12593.
• Aksu EH, Kandemir FM, Yıldırım S, Küçükler S, Dörtbudak MB, Çağlayan C, Benzer F. Palliative effect of curcumin on doxorubicin‐induced testicular damage in male rats J Biochem Mol Toxic. 2019; 33:e22384.
• Basheer AS, Siddiqui A, Paudel YN, Hassan MQ, Imran M, Najmi AK, Akhtar M. Hepatoprotective and antioxidant effects of fish oil on isoniazid-rifampin induced hepatotoxicity in rats PharmaNutrition 2017; 5:29-33.
• Benzer F, Kandemir FM, Kucukler S, Comaklı S, Caglayan C. Chemoprotective effects of curcumin on doxorubicin-induced nephrotoxicity in wistar rats: by modulating inflammatory cytokines, apoptosis, oxidative stress and oxidative DNA damage Arch Physiol Biochem. 2018; 124:448-457.
• Benzer F, Kandemir FM, Ozkaraca M, Kucukler S, Caglayan C. Curcumin ameliorates doxorubicin‐induced cardiotoxicity by abrogation of inflammation, apoptosis, oxidative DNA damage, and protein oxidation in rats J Biochem Mol Toxic. 2018; 32:e22030.
• Caglayan C, Kandemir FM, Darendelioğlu E, Yıldırım S, Kucukler S, Dortbudak MB. Rutin ameliorates mercuric chloride-induced hepatotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis J Trace Elem Med Bio. 2019; 56:60-68.
• Camus P, Fanton A, Bonniaud P, Camus C, Foucher P. Interstitial lung disease induced by drugs and radiation Respiration 2004; 71:301-326.
• Chepelev NL et al. Competition of nuclear factor-erythroid 2 factors related transcription factor isoforms, Nrf1 and Nrf2, in antioxidant enzyme induction Redox Biol. 2013; 1:183-189.
• Cho YJ, Park SB, Han M. Di-(2-ethylhexyl)-phthalate induces oxidative stress in human endometrial stromal cells in vitro Mol Cell Endocrinol. 2015; 407:9-17.
• Choi YH. Activation of the Nrf2/HO-1 signaling pathway contributes to the protective effects of coptisine against oxidative stress-induced DNA damage and apoptosis in HaCaT keratinocytes Gen Physiol Biophys. 2019; 38:281.
• Chowdhury A, Santra A, Bhattacharjee K, Ghatak S, Saha DR, Dhali GK. Mitochondrial oxidative stress and permeability transition in isoniazid and rifampicin induced liver injury in mice J Hepatol. 2006; 45:117-126.
• Combrink M, du Preez I. Metabolomics describes previously unknown toxicity mechanisms of isoniazid and rifampicin Toxicol Lett. 2020;
• Cunha L, Rodrigues S, Rosa da Costa AM, Faleiro L, Buttini F, Grenha A. Inhalable chitosan microparticles for simultaneous delivery of isoniazid and rifabutin in lung tuberculosis treatment Drug Dev Ind Pharm.i 2019; 45:1313-1320.
• Çelik H, Kandemir FM, Caglayan C, Özdemir S, Çomaklı S, Kucukler S, Yardım A. Neuroprotective effect of rutin against colistin-induced oxidative stress, inflammation and apoptosis in rat brain associated with the CREB/BDNF expressions Mol Biol Rep. 2020; 47:2023-2034.
• Çelik H, Kucukler S, Çomaklı S, Özdemir S, Caglayan C, Yardım A, Kandemir FM. Morin attenuates ifosfamide-induced neurotoxicity in rats via suppression of oxidative stress, neuroinflammation and neuronal apoptosis NeuroToxicology 2020; 76:126-137.
• Dai C et al. Curcumin attenuates quinocetone induced apoptosis and inflammation via the opposite modulation of Nrf2/HO-1 and NF-kB pathway in human hepatocyte L02 cells Food Chem Toxicol. 2016; 95:52-63.
• Eftekhari A, Heidari R, Ahmadian E, Eghbal MA. Cytoprotective Properties of Carnosine against Isoniazid-Induced Toxicity in Primary Cultured Rat Hepatocytes Pharm Sci. 2018; 24:257.
• Eldutar E, Kandemir FM, Kucukler S, Caglayan C. Restorative effects of Chrysin pretreatment on oxidant–antioxidant status, inflammatory cytokine production, and apoptotic and autophagic markers in acute paracetamol‐induced hepatotoxicity in rats: An experimental and biochemical study J Biochem Mol Toxic. 2017; 31:e21960.
• Guzmán-Beltrán S, Espada S, Orozco-Ibarra M, Pedraza-Chaverri J, Cuadrado A. Nordihydroguaiaretic acid activates the antioxidant pathway Nrf2/HO-1 and protects cerebellar granule neurons against oxidative stress Neurosci Lett. 2008; 447:167-171.
• Jia Z-l et al. Mechanism of isoniazid-induced hepatotoxicity in zebrafish larvae: Activation of ROS-mediated ERS, apoptosis and the Nrf2 pathway Chemo. 2019; 227:541-550.
• Jin SW et al. Protective effect of rutaecarpine against t-BHP-induced hepatotoxicity by upregulating antioxidant enzymes via the CaMKII-Akt and Nrf2/ARE pathways Food Chem Toxicol. 2017; 100:138-148.
• Kandemir FM, Yıldırım S, Kucukler S, Caglayan C, Darendelioğlu E, Dortbudak MB. Protective effects of morin against acrylamide-induced hepatotoxicity and nephrotoxicity: A multi-biomarker approach Food Chem Toxicol. 2020; 138:111190.
• Kandemir FM, Yıldırım S, Kucukler S, Caglayan C, Darendelioğlu E, Dortbudak MB. (b) Protective effects of morin against acrylamide-induced hepatotoxicity and nephrotoxicity: A multi-biomarker approach Food Chem Toxicol. 2020; 111190.
• Karakurt Y, Süleyman H, Keskin Cimen F, Tasli G, Ucak T, Icel E, Kurt N. The effects of lutein on optic nerve injury induced by ethambutol and isoniazid: an experimental study Cutan Ocul Toxicol. 2019; 38:136-140.
• Liang Z, Ni R, Zhou J, Mao S. Recent advances in controlled pulmonary drug delivery Drug Discov. Today. 2015; 20:380-389.
• Liu F, Wang L-Y, Yu M-C, Li Y-T, Wu Z-Y, Yan C-W. A new cocrystal of isoniazid-quercetin with hepatoprotective effect: The design, structure, and in vitro/in vivo performance evaluation Eur J Pharm. SCI 2020;105216.
• Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method Methods 2001; 25:402-408.
• Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent J Biol Chem. 1951; 193:265-275.
• 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; 27:7910-7921.
• Matkovics B. Determination of enzyme activity in lipid peroxidation and glutathione pathways Lab Diag. 1988; 15:248-250.
• Mehri S, Karami HV, Hassani FV, Hosseinzadeh H. Chrysin reduced acrylamide-induced neurotoxicity in both in vitro and in vivo assessments Iran Biomed J. 2014; 18:101.
• Organization WH. Global tuberculosis report 2013. WHO,
• Papiris SA, Triantafillidou C, Kolilekas L, Markoulaki D, Manali ED. Amiodarone Curr Drug Saf. 2010; 33:539-558.
• Park EJ, Kim YM, Park SW, Kim HJ, Lee JH, Lee D-U, Chang KC. Induction of HO-1 through p38 MAPK/Nrf2 signaling pathway by ethanol extract of Inula helenium L. reduces inflammation in LPS-activated RAW 264.7 cells and CLP-induced septic mice Food Chem Toxicol. 2013; 55:386-395.
• Placer ZA, Cushman LL, Johnson BC. Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems Anal Biochem. 1966; 16:359-364
• Raghu R, Karthikeyan S. Zidovudine and isoniazid induced liver toxicity and oxidative stress: Evaluation of mitigating properties of silibinin Environ Toxicol Pharmacol. 2016; 46:217-226.
• Ruan L-Y et al. Isoniazid-induced hepatotoxicity and neurotoxicity in rats investigated by 1H NMR based metabolomics approach Toxicol Lett. 2018; 295:256-269.
• Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress Curr Biol. 2014; 24:R453-R462.
• Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent Anal Biochem. 1968; 25:192-205.
• Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase Clin Chem. 1988; 34:497-500.
• Surh Y-J, Kundu JK, Na H-K. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals Planta Med. 2008; 74:1526-1539.
• Terzo F, Ricci A, D'Ascanio M, Raffa S, Mariotta S. Amiodarone-induced pulmonary toxicity with an excellent response to treatment: A case report Respir Med Case Rep. 2020; 29:100974.
• Verma AK, Yadav A, Singh SV, Mishra P, Rath SK. Isoniazid induces apoptosis: Role of oxidative stress and inhibition of nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) Life Sci. 2018; 199:23-33.
• Vilchèze C, Jacobs Jr WR. The isoniazid paradigm of killing, resistance, and persistence in Mycobacterium tuberculosis J Mol Biol. 2019; 431:3451-3461.
• Wali AF, Mushtaq A, Rehman MU, Akbar S, Masoodi MH. Amelioration of Rifampicin and Isoniazid Induced Liver Oxidative Damage and Inflammation Response by Propolis Extracts in Rodent Model Jou of Biolo Acti Prod from Nat 2019; 9:57-66.
• Wang J et al. Sagittaria sagittifolia polysaccharide protects against isoniazid-and rifampicin-induced hepatic injury via activation of nuclear factor E2-related factor 2 signaling in mice J Ethnopharmacol. 2018; 227:237-245.
• Xiang N, Zhao C, Diao X, Han Q, Zhou H. Dynamic responses of antioxidant enzymes in pearl oyster Pinctada martensii exposed to di (2-ethylhexyl) phthalate (DEHP) Environ Toxicol Pharmacol. 2017; 54:184-190.
• You H, Chen S, Mao L, Li B, Yuan Y, Li R, Yang X. The adjuvant effect induced by di-(2-ethylhexyl) phthalate (DEHP) is mediated through oxidative stress in a mouse model of asthma Food Chem Toxicol. 2014; 71:272-281.
• Zhang D, Xiao Y, Lv P, Teng Z, Dong Y, Qi Q, Liu Z. Edaravone attenuates oxidative stress induced by chronic cerebral hypoperfusion injury: role of ERK/Nrf2/HO-1 signaling pathway Neurol Res. 2018; 40:1-10.
• Zhang Q, Zhao Y, Talukder M, Han Y, Zhang C, Li X-N, Li J-L. Di (2-ethylhexyl) phthalate induced hepatotoxicity in quail (Coturnix japonica) via modulating the mitochondrial unfolded protein response and NRF2 mediated antioxidant defense Sci. Total Environ. 2019; 651:885-894.
• Zhang Y et al. SIRT1 alleviates isoniazid-induced hepatocyte injury by reducing histone acetylation in the IL-6 promoter region Int Immunopharmacol. 2019; 67:348-355.
• Zhang Z, Guo Z, Zhan Y, Li H, Wu S. Role of histone acetylation in activation of nuclear factor erythroid 2-related factor 2/heme oxygenase 1 pathway by manganese chloride Toxicol Appl Pharmacol. 2017; 336:94-100.