Expression Profile of Markers of Apoptosis, Injury and Oxidative Stress in Human Lung Epithelium Cells"‘A5449 Receiving Chronic Exposure of Potential Anti"‘Tubercular Drug"‘trans"‘Cyclohexane"‘1, 4"‘Diamine Derivative"‘”9u”

Jump To References Section

Authors

  • ,IN
  • ,IN
  • ,IN
  • ,IN
  • ,IN

Keywords:

A549 cell line, apoptosis, injury, Mycobacterium tuberculosis, oxidative stress

Abstract

Earlier, we had reported the synthesis of a library of symmetrical trans"‘cyclohexane"‘1,4"‘diamine derivatives and evaluated them for their anti"‘mycobacterium activity in the H37RV strain of Mycobacterium tuberculosis. A range of efficacy was recorded in different derivatives and the compound "9u” having an i"‘propyl group substitution at the p"‘position was found to be the most effective. The compound "9u” was found to be safe for cytotoxic and genotoxic responses in human lung epithelium cells"‘A549, even up to many fold higher than that required to kill M. tuberculosis. Hence, compound "9u” was inferred to be a potential anti"‘tuberculosis drug of choice. However, the biological safety of compound "9u” upon chronic exposure was still to be answered because anti"‘tuberculosis (TB) treatment requires a minimum of 6 months' exposure of host systems and most of the available anti"‘TB drugs are known to induce apoptosis, oxidative stress and injury during such exposures. Thus, the present investigations were aimed to study the alterations, if any, in the expression profile (mRNA and protein) of markers associated with apoptosis, injury and oxidative stress in human lung epithelium cells"‘A549 receiving a chronic exposure of the potential anti"‘TB compound "9u.” Our findings demonstrate that there was a statistically insignificant transient shift (until 3 weeks) in the markers of apoptosis, injury and oxidative stress, after which expression changes were similar to baseline, when compared with unexposed cells of respective time periods. The studied markers showed linearity in the trend at both mRNA and protein level, indicating the suitability of the test system selected in the study. The data confirm the therapeutic potential of compound "9u” for even long"‘term treatment against M. tuberculosis without having any significant apoptosis, injury and oxidative stress.

Downloads

Download data is not yet available.

Published

2018-04-26

How to Cite

Kapoor, E., Tripathi, V., Kumar, V., Juyal, V., Bhagat, S., & Ram, V. (2018). Expression Profile of Markers of Apoptosis, Injury and Oxidative Stress in Human Lung Epithelium Cells"‘A5449 Receiving Chronic Exposure of Potential Anti"‘Tubercular Drug"‘trans"‘Cyclohexane"‘1, 4"‘Diamine Derivative"‘”9u”. Toxicology International, 21(2), 172–178. Retrieved from http://www.informaticsjournals.com/index.php/toxi/article/view/21001

Issue

Section

Original Research
Received 2018-04-26
Accepted 2018-04-26
Published 2018-04-26

 

References

Pai M, Sharma SK. Editorial"‘ Are we providing quality care to our patients with tuberculosis? Indian J Med Res 2007;125:491"‘7.

News item. Scientists find cure for extreme TB strain. Combination of two FDA"‘approved drugs blocks growth of TB strain. Pune, India: The Times of India; 2009. p. 7.

ICMR. What is new in the diagnosis of tuberculosis? Part 1. Techniques for diagnosis of tuberculosis. ICMR Bull 2002;32:69"‘76.

Editorial. The tuberculosisxfactor. Lancet 2006;6:679.

O'Hara P, Hickey AJ. Respirable PLGA microspheres containing rifamycin for the treatment of tuberculosis: Manufacture and characterization. Pharm Res 2000;17:955"‘61.

Pandey R, Khuller GK. Antitubercular inhaled therapy: Opportunities, progress and challenges. J Antimicrob Chemother 2005;55:430"‘5.

Sharma R, Muttil P, Yadav AB, Rath SK, Bajpai VK, Mani U, et al. Uptake of inhalable microparticles affects defence responses of macrophages infected with Mycobacterium tuberculosis H37Ra.

J Antimicrob Chemother 2007;59:499"‘506.

Sharma R, Saxena D, Dwivedi AK, Misra A. Inhalable microparticles containing drug combinations to target alveolar macrophages for treatment of pulmonary tuberculosis. Pharm Res 2001;18:1405"‘10.

Suarez S, O'Hara P, Kazantseva M, Newcomer CE, Hopfer R, McMurray DN, et al. Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: Screening in an infectious disease model. Pharm Res 2001;18:1315"‘9.

Cynamon MH, Zhang Y, Harpster T, Cheng S, DeStefano MS.High"‘dose isoniazid therapy for isoniazid"‘resistant murine Mycobacterium tuberculosis infection. Antimicrob Agents Chemother 1999;43:2922"‘4.

Langton ME, Cowie RL. Failure of a prothionamide"‘containing oral antituberculosis regimen. S Afr Med J 1985;68:881.

Muttil P, Kaur J, Kumar K, Yadav AB, Sharma R, Misra A. Inhalable microparticles containing large payload of anti"‘tuberculosis drugs. Eur J Pharm Sci 2007;32:140"‘50.

Prior S, Gander B, Blarer N, Merkle H, Subira M, Irache J, et al. In vitro phagocytosis and monocyte"‘macrophage activation with poly (lactide) and poly (lactide"‘co"‘glycolide) microspheres. Eur J Pharm Sci 2000;15:197"‘207.

Schnyder J, Baggiolini M. Role of phagocytosis in the activation of macrophages. J Exp Med 1978;148:1449"‘57.

Gan H, He X, Duan L, Mirabile"‘Levens E, Kornfeld H, Remold HG.Enhancement of antimycobacterial activity of macrophages by stabilization of inner mitochondrial membrane potential. J Infect Dis 2005;191:1292"‘300.

Lee J, Remold HG, Ieong MH, Kornfeld H. Macrophage apoptosis in response to high intracellular burden of Mycobacterium tuberculosis is mediated by a novel caspase"‘independent pathway. J Immunol 2006;176:4267"‘74.

Volker B, Jessica LM. Living on the edge: Inhibition of host cell apoptosis by Mycobacterium tuberculosis. Future Microbiol 2008;3:415"‘22.

Bhadauria S, Mishra R, Kanchan R, Tripathi C, Srivastava A, Tiwari A, et al. Isoniazid"‘induced apoptosis in HepG2 cells: Generation of oxidative stress and Bcl"‘2 down"‘regulation.Toxicol Mech Methods 2010;20:242"‘51.

Kumar N, Kapoor E, Singh R, Kidwai S, Kumbukgolla W, Bhagat S, et al. Synthesis and antibacterial/antitubercular activity evaluation of symmetrical trans"‘cyclohexane"‘1,4"‘diamine derivatives. Indian J Chem 2013;52B: 1441"‘50.

Kapoor E, Tripathi V, Kumar V, Juyal V, Bhagat S, Ram V.Cyto"‘genotoxicity Assessment of Potential Anti"‘tubercular Drug Candidate Molecule"‘trans"‘cyclohexane"‘1, 4"‘diamine Derivative"‘”9u” in Human Lung Epithelial Cells A549. Toxicol Int 2014;21:69"‘77.

Kashyap MP, Singh AK, Kumar V, Tripathi VK, Srivastava RK, Agrawal M, et al. Monocrotophos induced apoptotic changes in PC12 cells: Involvement of xenobiotic metabolizing cytochrome P450s. PLOs One 2011;6:e17757.

Schaberg T, Rebhan K, Lode H. Risk factors for side effects of isoniazid rifampicin and pyrazinamide in patients hospitalized for pulmonary tuberculosis. Eur Respir J 1996;9:2026"‘30.

Dash LA, Comstock GW, Flynn PG. Isoniazid preventive therapy: Retrospect and prospect. Am Rev Respir Dis 1980;121:1039"‘44.

Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first"‘line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 2003;167:1472"‘7.

Tasduq SA, Peerzada K, Koul S, Bhat R, Johri RK. Biochemical manifestations of anti"‘tuberculosis drugs induced hepatotoxicity and the effect of silymarin. Hepatol Res 2005;31:132"‘5.

British Medical Research Council (Hong Kong Chest Service). Controlled trial of 2, 4 and 6 months of pyrazinamide in 6 month, three times weekly regimens for smear positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin and pyrazinamide. Ann Rev Respir Dis 1991;143:700"‘6.

British Medical Research Council (Singapore Tuberculosis Service). Assessment of a daily combined preparation of isoniazid, rifampin, and pyrazinamide in a controlled trial of three 6 month regimens for smear positive pulmonary tuberculosis. Ann Rev Respir Dis 1991;143:707"‘12.

Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampicin. Chest 1991;99:465"‘71.

Tostmann A, Boeree MJ, Aarnoutse RE, de Lange WC, van der Ven AJ, Dekhuijzen R. Anti"‘tuberculosis drug"‘induced hepatotoxicity: Concise up to date review. J Gastroenterol Hep 2008;23:192"‘202.

Kinzig"‘Schippers M. Should we use N"‘acetyltransferase genotyping to personalize isoniazid doses? Antimicrob Agents Chemother 2005;49:1733"‘8.

Mitchell JR, Zimmerman HJ, Ishak GG. Isoniazid liver injury: Clinical spectrum, pathology and probable pathogenesis. Am Intern Med 1976;84:181"‘92.

Timbrell JA, Scales MD, Streeter AJ. Studies on hydrazine Hepatotoxicity, 2 biochemical findings. J Toxicol Environ Health 1982;10:955"‘68.

Sodhi CP, Rana SV, Mehta SK, Vaiphei K, Attri S, Mehta SK. Study of oxidative stress in isoniazid"‘rifampicin induced hepatic injury in young rats. Drug Chem Toxicol 1997;20:255"‘69.

Sodhi CP, Rana SV, Attri S, Mehta S, Vaiphei K, Mehta SK. Oxidative"‘hepatic injury of isoniazid"‘rifampicin in young rats subjected to protein and energy malnutrition. Drug Chem Toxicol 1998;21:305"‘17.

Li AP, Rieht MK, Rasmussen A, Goski JC, Hall SD, Xu L, et al. Primary human hepatocytes as a tool for the evaluation of structure"‘activity relationship in cytochrome P450 induction potential of xenobiotics: Evaluation of rifampin, rifapentine and rifabutin. Chem Biol Interat 1997;107:17"‘30.

Nelson SD, Mitchell JR, Timbrell JA, Snodgrass WR, Corcoran GB. III Isoniazid and iproniazid: Activation of metabolites to toxic intermediates in man and rat. Science 1976;193:901"‘3.

Leach KL, Brickner SJ, Noe MC, Miller PF. Linezolid, the first oxazolidinone antibacterial agent. Ann N Y Acad Sci 2011;1222:49"‘54.

Ippolito JA, Kanyo ZF, Wang D, Franceschi FJ, Moore PB, Steitz TA, et al. Crystal structure of the oxazolidinone antibiotic linezolid bound to the 50S ribosomal subunit. J Med Chem 2008;51:3353"‘6.

Vinh DC, Rubinstein E. Linezolid: A review of safety and tolerability. J Infect 2009;59 Suppl 1:S59"‘74.

Di Paolo A, Malacarne P, Guidotti E, Danesi R, Del Tacca M. Pharmacological issues of linezolid: An updated critical review. Clin Pharmacokinet 2010;49:439"‘47.

Lee E, Burger S, Shah J, Melton C, Mullen M, Warren F, et al. Linezolid"‘associated toxic optic neuropathy: A report of 2 cases. Clin Infect Dis 2003;37:1389"‘91.

Beekmann SE, Gilbert DN, Polgreen PM; IDSA Emerging Infections Network. Toxicity of extended courses of linezolid: Results of an Infectious Diseases Society of America Emerging Infections Network survey. Diagn Microbiol Infect Dis 2008;62:407"‘10.

Nagiec EE, Wu L, Swaney SM, Chosay JG, Ross DE, Brieland JK, et al. Oxazolidinones inhibit cellular proliferation via inhibition of mitochondrial protein synthesis. Antimicrob Agents Chemother 2005;49:3896"‘902.

Mitchell JR, Thorgeirsson UP, Black M, Timbrell JA, Snodgrass WR, Potter WZ, et al. Increased incidence of isoniazid hepatitis in rapid acetylators: Possible relation to hydrazine metabolites.

Clin Pharmacol Ther 1975;18:70"‘9.

Attri S, Rana SV, Vaiphie K, Katyal R, Sodhi CP, Kanwar S, et al.Protective effect of N"‘acetylcysteine in isoniazid induced hepatic injury in growing rats. Indian J Exp Biol 2001;39:436"‘40.

Russell DG, Mwandumba HC, Rhoades EE. Mycobacterium and the coat of many lipids. J Cell Biol 2002;158:421"‘6.

Ernst JD. Macrophage receptors for Mycobacterium tuberculosis.Infect Immun 1998;66:1277"‘81.

Cegielski JP. Extensively drug"‘resistant tuberculosis: "There must be some kind of way out of here”. Clin Infect Dis 2010;50 Suppl 3:S195"‘200.

Strolin Benedetti M, Dostert P. Induction and auto"‘induction properties of rifamycin derivatives: A review of animal and human studies. Environ Health Perspect 1994;102 Suppl 9:101"‘5.

Grosset JH, Singer TG, Bishai WR. New drugs for the treatment of tuberculosis: Hope and reality. Int J Tuberc Lung Dis 2012;16:1005"‘14.

Mitchison D, Davies G. The chemotherapy of tuberculosis: Past, present and future. Int J Tuberc Lung Dis 2012;16:724"‘32.

Kolpakova TA, Kolpakov MA, Bashkirova IuV, Rachkovskaia LN, Burylin SIu, Liubarskić­ MS. Effects of the enterosorbent SUMS"‘1 on isoniazid pharmacokinetics and lipid peroxidation in patients with pulmonary tuberculosis and drug"‘induced hepatic lesions. Probl Tuberk 2001;3:34"‘6.