Genetic Variants and Drug Efficacy in Tuberculosis: A Step toward Personalized Therapy

Abstract

Tuberculosis (TB) continues to be a major infectious disease affecting individuals worldwide. Current TB treatment strategy recommends the standard short-course chemotherapy regimen containing first-line drug, i.e., isoniazid, rifampicin, pyrazinamide, and ethambutol to treat patients suffering from drug-susceptible TB. Although Mycobacterium tuberculosis, the causing agent, is susceptible to drugs, some patients do not respond to the treatment or treatment may result in serious adverse reactions. Many studies revealed that anti-TB drug-related toxicity is associated with genetic variations, and these variations may also influence attaining maximum drug concentration. Thus, inter-individual diversities play a characteristic role by influencing the genes involved in drug metabolism pathways. The development of pharmacogenomics could bring a revolution in the field of treatment, and the understanding of germline variants may give rise to optimized targeted treatments and refine the response to standard therapy. In this review, we briefly introduced the field of pharmacogenomics with the evolution in genetics and discussed the pharmacogenetic impact of genetic variations on genes involved in the activities, such as anti-TB drug transportation, metabolism, and gene regulation.

Keywords

mycobacterium tuberculosis / germline variants / anti-TB drug-related toxicity / pharmacogenomics / personalized medicine

References

[1] Barberis I, Bragazzi NL, Galluzzo L, Martini M.The history of tuberculosis: from the first historical records to the isolation of Koch's bacillus. J Prev Med Hyg 2017; 58(01): E9-E12

[2] World Health Organisation report, 2020. Accessed September 27, 2021 at: https://apps.who.int/iris/bitstream/handle/10665/336069/9789240013131-eng.pdf

[3] Ramamoorthy A, Pacanowski MA, Bull J, Zhang L.Racial/ethnic differences in drug disposition and response: review of recently approved drugs. Clin Pharmacol Ther 2015; 97(03): 263-273

[4] Relling MV, Giacomini KM.Pharmacogenetics. In: Brunton LL, Lazo GS, Parker KL. eds. Goodman & Gilman's. The Pharmacological Basis of Therapeutics, XI edizione. New York: McGraw-Hill Medical Publishing Division; 2006. , chapter 4: 93-115

[5] Bachtiar M, Ooi BNS, Wang J.et al.Towards precision medicine: interrogating the human genome to identify drug pathways associated with potentially functional, population-differentiated polymorphisms. Pharmacogenomics J 2019; 19(06): 516-527

[6] Barbarino JM, Whirl-Carrillo M, Altman RB, Klein TE.PharmGKB: a worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med 2018; 10(04): e1417

[7] O'Donnell PH, Dolan ME. Cancer pharmacoethnicity: ethnic differences in susceptibility to the effects of chemotherapy. Clin Cancer Res 2009; 15(15): 4806-4814

[8] Getahun H, Matteelli A, Abubakar I.et al.Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries. Eur Respir J 2015; 46(06): 1563-1576

[9] Dompreh A, Tang X, Zhou J.et al.Effect of genetic variation of NAT2 on isoniazid and SLCO1B1 and CES2 on rifampin pharmacokinetics in Ghanaian children with tuberculosis. Antimicrob Agents Chemother 2018; 62(03): e02099-17

[10] Metushi IG, Cai P, Zhu X, Nakagawa T, Uetrecht JP.A fresh look at the mechanism of isoniazid-induced hepatotoxicity. Clin Pharmacol Ther 2011; 89(06): 911-914

[11] Carlson HB, Anthony EM, Russell Jr WF, Middlebrook G.Prophylaxis of isoniazid neuropathy with pyridoxine. N Engl J Med 1956; 255(03): 119-122

[12] Lander ES, Linton LM, Birren B.et al; International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 2001; 409(6822): 860-921

[13] Venter JC, Adams MD, Myers EW.et al.The sequence of the human genome. Science 2001; 291(5507): 1304-1351

[14] Wilke RA, Lin DW, Roden DM.et al.Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov 2007; 6(11): 904-916

[15] Court MH.A pharmacogenomics primer. J Clin Pharmacol 2007; 47(09): 1087-1103

[16] Sloan DJ, McCallum AD, Schipani A. et al. Genetic determinants of the pharmacokinetic variability of rifampin in Malawian adults with pulmonary tuberculosis. Antimicrob Agents Chemother 2017; 61(07): e00210-e00217

[17] Thomas L, Miraj SS, Surulivelrajan M, Varma M, Sanju CSV, Rao M.Influence of single nucleotide polymorphisms on rifampin pharmacokinetics in tuberculosis patients. Antibiotics (Basel) 2020; 9(06): 307

[18] Weber WW, Hein DW.Clinical pharmacokinetics of isoniazid. Clin Pharmacokinet 1979; 4(06): 401-422

[19] Murray JF, Schraufnagel DE, Hopewell PC.Treatment of tuberculosis. A historical perspective. Ann Am Thorac Soc 2015; 12(12): 1749-1759

[20] Maggi N, Pasqualucci CR, Ballotta R, Sensi P.Rifampicin: a new orally active rifamycin. Chemotherapy 1966; 11(05): 285-292

[21] Campbell EA, Korzheva N, Mustaev A.et al.Structural mechanism for rifampicin inhibition of bacterial RNA polymerase. Cell 2001; 104(06): 901-912

[22] Zaw MT, Emran NA, Lin Z.Mutations inside rifampicin-resistance determining region of rpoB gene associated with rifampicin-resistance in Mycobacterium tuberculosis. J Infect Public Health 2018; 11(05): 605-610

[23] Gumbo T, Louie A, Deziel MR.et al.Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin. Antimicrob Agents Chemother 2007; 51(11): 3781-3788

[24] Stott KE, Pertinez H, Sturkenboom MGG.et al.Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis. J Antimicrob Chemother 2018; 73(09): 2305-2313

[25] Seijger C, Hoefsloot W, Bergsma-de Guchteneire I. et al. High-dose rifampicin in tuberculosis: experiences from a Dutch tuberculosis centre. PLoS One 2019; 14(03): e0213718

[26] Svensson EM, Svensson RJ, Te Brake LHM.et al.The potential for treatment shortening with higher rifampicin doses: relating drug exposure to treatment response in patients with pulmonary tuberculosis. Clin Infect Dis 2018; 67(01): 34-41

[27] Kim RB.Organic anion-transporting polypeptide (OATP) transporter family and drug disposition. Eur J Clin Invest 2003; 33(Suppl. 02): 1-5

[28] Tirona RG, Leake BF, Wolkoff AW, Kim RB.Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation. J Pharmacol Exp Ther 2003; 304(01): 223-228

[29] Liederer BM, Borchardt RT.Enzymes involved in the bioconversion of ester-based prodrugs. J Pharm Sci 2006; 95(06): 1177-1195

[30] Nakajima A, Fukami T, Kobayashi Y, Watanabe A, Nakajima M, Yokoi T.Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: rifampicin, rifabutin, and rifapentine. Biochem Pharmacol 2011; 82(11): 1747-1756

[31] Boivin AA, Cardinal H, Barama A, Pichette V, Hébert MJ, Roger M.Organic anion transporting polypeptide 1B1 (OATP1B1) and OATP1B3: genetic variability and haplotype analysis in white Canadians. Drug Metab Pharmacokinet 2010; 25(05): 508-515

[32] Giacomini KM, Huang SM, Tweedie DJ.et al; International Transporter Consortium. Membrane transporters in drug development. Nat Rev Drug Discov 2010; 9(03): 215-236

[33] Niemi M.Role of OATP transporters in the disposition of drugs. Pharmacogenomics 2007; 8(07): 787-802

[34] Vavricka SR, Van Montfoort J, Ha HR, Meier PJ, Fattinger K.Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Hepatology 2002; 36(01): 164-172

[35] Hillgren KM, Keppler D, Zur AA.et al; International Transporter Consortium. Emerging transporters of clinical importance: an update from the International Transporter Consortium. Clin Pharmacol Ther 2013; 94(01): 52-63

[36] Guo YX, Xu XF, Zhang QZ.et al.The inhibition of hepatic bile acids transporters Ntcp and Bsep is involved in the pathogenesis of isoniazid/rifampicin-induced hepatotoxicity. Toxicol Mech Methods 2015; 25(05): 382-387

[37] Te Brake LH, Russel FG, van den Heuvel JJ. et al. Inhibitory potential of tuberculosis drugs on ATP-binding cassette drug transporters. Tuberculosis (Edinb) 2016; 96: 150-157

[38] Internet source. Accessed on September 1, 2021 at: www.hapman.com

[39] Oshiro C, Mangravite L, Klein T, Altman R.PharmGKB very important pharmacogene: SLCO1B1. Pharmacogenet Genomics 2010; 20(03): 211-216

[40] Niemi M, Pasanen MK, Neuvonen PJ.Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev 2011; 63(01): 157-181

[41] Allegra S, Fatiguso G, Calcagno A.et al.Role of vitamin D pathway gene polymorphisms on rifampicin plasma and intracellular pharmacokinetics. Pharmacogenomics 2017; 18(09): 865-880

[42] Weiner M, Peloquin C, Burman W.et al.Effects of tuberculosis, race, and human gene SLCO1B1 polymorphisms on rifampin concentrations. Antimicrob Agents Chemother 2010; 54(10): 4192-4200

[43] Lee HH, Ho RH.Interindividual and interethnic variability in drug disposition: polymorphisms in organic anion transporting polypeptide 1B1 (OATP1B1; SLCO1B1). Br J Clin Pharmacol 2017; 83(06): 1176-1184

[44] Dompreh A, Tang X, Zhou J.et al.Effect of genetic variation of NAT2 on isoniazid and SLCO1B1 and CES2 on rifampin pharmacokinetics in Ghanaian children with tuberculosis. Antimicrob Agents Chemother 2018; 62(03): e02099-e17

[45] Chigutsa E, Visser ME, Swart EC.et al.The SLCO1B1 rs4149032 polymorphism is highly prevalent in South Africans and is associated with reduced rifampin concentrations: dosing implications. Antimicrob Agents Chemother 2011; 55(09): 4122-4127

[46] Gengiah TN, Botha JH, Soowamber D, Naidoo K, Abdool Karim SS.Low rifampicin concentrations in tuberculosis patients with HIV infection. J Infect Dev Ctries 2014; 8(08): 987-993

[47] Schuetz EG, Schinkel AH, Relling MV, Schuetz JD.P-glycoprotein: a major determinant of rifampicin-inducible expression of cytochrome P4503A in mice and humans. Proc Natl Acad Sci USA 1996; 93(09): 4001-4005

[48] Jones PM, George AM.The ABC transporter structure and mechanism: perspectives on recent research. Cell Mol Life Sci 2004; 61(06): 682-699

[49] Gottesman MM, Hrycyna CA, Schoenlein PV, Germann UA, Pastan I.Genetic analysis of the multidrug transporter. Annu Rev Genet 1995; 29: 607-649

[50] Wolking S, Schaeffeler E, Lerche H, Schwab M, Nies AT.Impact of genetic polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on drug disposition and potential clinical implications: update of the literature. Clin Pharmacokinet 2015; 54(07): 709-735

[51] Caraba A, Crişan V, Romoşan I, Mozoş I, Murariu M.Vitamin D status, disease activity, and endothelial dysfunction in early rheumatoid arthritis patients. Dis Markers 2017; 2017: 5241012

[52] Hodges LM, Markova SM, Chinn LW.et al.Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics 2011; 21(03): 152-161

[53] Fung KL, Gottesman MM.A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim Biophys Acta 2009; 1794(05): 860-871

[54] Jinno H, Tanaka-Kagawa T, Hanioka N.et al.Identification of novel alternative splice variants of human constitutive androstane receptor and characterization of their expression in the liver. Mol Pharmacol 2004; 65(03): 496-502

[55] Jamis-Dow CA, Katki AG, Collins JM, Klecker RW.Rifampin and rifabutin and their metabolism by human liver esterases. Xenobiotica 1997; 27(10): 1015-1024

[56] Ross MK, Crow JA.Human carboxylesterases and their role in xenobiotic and endobiotic metabolism. J Biochem Mol Toxicol 2007; 21(04): 187-196

[57] Wang D, Zou L, Jin Q, Hou J, Ge G, Yang L.Human carboxylesterases: a comprehensive review. Acta Pharm Sin B 2018; 8(05): 699-712

[58] Merali Z, Ross S, Paré G.The pharmacogenetics of carboxylesterases: CES1 and CES2 genetic variants and their clinical effect. Drug Metabol Drug Interact 2014; 29(03): 143-151

[59] Song SH, Chang HE, Jun SH.et al.Relationship between CES2 genetic variations and rifampicin metabolism. J Antimicrob Chemother 2013; 68(06): 1281-1284

[60] Mitchison DA.Plasma concentrations of isoniazid in the treatment of tuberculosis. In: Davies DS, Prichard BN. eds. Biological Effects of Drugs in Relation to their Plasma Concentrations. London: MacMillan; 1973: 171-182

[61] Ellard GA, Gammon PT.Pharmacokinetics of isoniazid metabolism in man. J Pharmacokinet Biopharm 1976; 4(02): 83-113

[62] Bhandari R, Kaur IP.Pharmacokinetics, tissue distribution and relative bioavailability of isoniazid-solid lipid nanoparticles. Int J Pharm 2013; 441(1-2): 202-212

[63] Hutchings AD, Monie RD, Spragg BP, Routledge PA.Saliva and plasma concentrations of isoniazid and acetylisoniazid in man. Br J Clin Pharmacol 1988; 25(05): 585-589

[64] Jutte PC, Rutgers SR, Van Altena R, Uges DR, Van Horn JR.Penetration of isoniazid, rifampicin and pyrazinamide in tuberculous pleural effusion and psoas abscess. Int J Tuberc Lung Dis 2004; 8(11): 1368-1372

[65] Conte Jr JE, Golden JA,McQuitty M. et al. Effects of gender, AIDS, and acetylator status on intrapulmonary concentrations of isoniazid. [published correction appears in Antimicrob Agents Chemother. 2002 Sep;46(9):3112.] Antimicrob Agents Chemother 2002; 46(08): 2358-2364

[66] Singh N, Golani A, Patel Z, Maitra A.Transfer of isoniazid from circulation to breast milk in lactating women on chronic therapy for tuberculosis. Br J Clin Pharmacol 2008; 65(03): 418-422

[67] Wang P, Pradhan K, Zhong XB, Ma X.Isoniazid metabolism and hepatotoxicity. Acta Pharm Sin B 2016; 6(05): 384-392

[68] Khan SR, Morgan AG, Michail K.et al.Metabolism of isoniazid by neutrophil myeloperoxidase leads to isoniazid-NAD(+) adduct formation: a comparison of the reactivity of isoniazid with its known human metabolites. Biochem Pharmacol 2016; 106: 46-55

[69] Rozwarski DA, Grant GA, Barton DH, Jacobs Jr WR, Sacchettini JC.Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis. Science 1998; 279(5347): 98-102

[70] Khan N, Pande V, Das A.NAT2 sequence polymorphisms and acetylation profiles in Indians. Pharmacogenomics 2013; 14(03): 289-303

[71] Preziosi P.Isoniazid: metabolic aspects and toxicological correlates. Curr Drug Metab 2007; 8(08): 839-851

[72] Cheng J, Krausz KW, Li F, Ma X, Gonzalez FJ.CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid. Toxicol Appl Pharmacol 2013; 266(02): 245-253

[73] Sim E, Payton M, Noble M, Minchin R.An update on genetic, structural and functional studies of arylamine N-acetyltransferases in eucaryotes and procaryotes. Hum Mol Genet 2000; 9(16): 2435-2441

[74] Blum M, Grant DM, McBride W, Heim M, Meyer UA. Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression. DNA Cell Biol 1990; 9(03): 193-203

[75] Ohsako S, Deguchi T.Cloning and expression of cDNAs for polymorphic and monomorphic arylamine N-acetyltransferases from human liver. J Biol Chem 1990; 265(08): 4630-4634

[76] Windmill KF, Gaedigk A, Hall PM, Samaratunga H, Grant DM, McManus ME. Localization of N-acetyltransferases NAT1 and NAT2 in human tissues. Toxicol Sci 2000; 54(01): 19-29

[77] Sabbagh A, Darlu P, Crouau-Roy B, Poloni ES.Arylamine N-acetyltransferase 2 (NAT2) genetic diversity and traditional subsistence: a worldwide population survey. PLoS One 2011; 6(04): e18507

[78] Boukouvala S, Sim E.Structural analysis of the genes for human arylamine N-acetyltransferases and characterisation of alternative transcripts. Basic Clin Pharmacol Toxicol 2005; 96(05): 343-351

[79] Hein DW.N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk. Oncogene 2006; 25(11): 1649-1658

[80] Richardson M, Kirkham J, Dwan K, Sloan D, Davies G, Jorgensen A.Influence of genetic variants on toxicity to anti-tubercular agents: a systematic review and meta-analysis (protocol). Syst Rev 2017; 6(01): 142

[81] Donald PR, Parkin DP, Seifart HI.et al.The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid. Eur J Clin Pharmacol 2007; 63(07): 633-639

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