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  • Original Article
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Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity

Abstract

Treatment of latent tuberculosis infection (LTBI) generally includes isoniazid (INH), a drug that can cause serious hepatotoxicity. Carboxylesterases (CES) are important in the metabolism of a variety of substrates, including xenobiotics. We hypothesized that genetic variation in CES genes expressed in the liver could affect INH-induced hepatotoxicity. Three CES genes are known to be expressed in human liver: CES1, CES2 and CES4. Our aim was to systematically characterize genetic variation in these novel candidate genes and test whether it is associated with this adverse drug reaction. As part of a pilot study, 170 subjects with LTBI who received only INH were recruited, including 23 cases with hepatotoxicity and 147 controls. All exons and the promoters of CES1, CES2 and CES4 were bidirectionally sequenced. A large polymorphic deletion was found to encompass exons 2 to 6 of CES4. No significant association was found. Eleven single-nucleotide polymorphisms (SNPs) in CES1 were in high linkage disequilibrium with each other. One of these SNPs, C(−2)G, alters the translation initiation sequence of CES1 and represents a candidate functional polymorphism. Replication of this possible association in a larger sample set and functional studies will be necessary to determine if this CES1 variant has a role in INH-induced hepatotoxicity.

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Abbreviations

INH:

isoniazid

ADRs:

adverse drug reactions

CES:

carboxylesterases

AST:

aspartate aminotransferase

OR:

odds ratio

UTR:

untranslated region

LD:

linkage disequilibrium.

References

  1. FitzGerald JM, Wang L, Elwood RK . Tuberculosis: control of the disease among aboriginal people in Canada. CMAJ 2000; 162: 351–355.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. FitzGerald JM . Optimizing tuberculosis control in the inner city. CMAJ 1999; 160: 821–822.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Hernandez E, Kumimoto D, Wang L, Rogrigues M, Black W, Elwood RK et al. Predictors for clustering among TB cases in Vancouver: a four year molecular epidemiology study. CMAJ 2002; 167: 349–352.

    Google Scholar 

  4. Durand F, Jebrak G, Pessayre D, Fournier M, Bernuau J . Hepatotoxicity of antitubercular treatments. Rationale for monitoring liver status. Drug Saf 1996; 15: 394–405.

    Article  CAS  PubMed  Google Scholar 

  5. Dossing M, Wilcke JT, Askgaard DS, Nybo B . Liver injury during antituberculosis treatment: an 11-year study. Tuber Lung Dis 1996; 77: 335–340.

    Article  CAS  PubMed  Google Scholar 

  6. Nolan CM, Goldberg SV, Buskin SE . Hepatotoxicity associated with isoniazid preventive therapy: a 7-survey from public health tuberculosis clinic. JAMA 1999; 281: 1014–1018.

    Article  CAS  PubMed  Google Scholar 

  7. Schaberg T, Gialdroni-Grassi G, Huchon G, Leophonte P, Manresa F, Woodhead M . An analysis of decisions by European general practitioners to admit to hospital patients with lower respiratory tract infections. The European Study Group of Community Acquired Pneumonia (ESOCAP) of the European Respiratory Society. Throax 1996; 51: 1017–1022.

    Article  CAS  Google Scholar 

  8. Hwang SJ, Lee SD, Li CP, Lu RH, Chan CY, Wu JC . Clinical Study of cryoglobulinaemia in Chinese patients with chronic hepatitis C. J Gastroenterol Hepatol 1997; 12: 513–517.

    Article  CAS  PubMed  Google Scholar 

  9. Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandon RK . Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax 1996; 51: 132–136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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: 1472–1477.

    Article  PubMed  Google Scholar 

  11. Steele MA, Burk RF, DesPrez RM . Toxic hepatitis with isoniazid and rifampin a meta-analysis. Chest 1991; 99: 465–471.

    Article  CAS  PubMed  Google Scholar 

  12. Saram GR, Imanuel C, Kailasam S, Narayana ASL, Venkatesan P . Rifampin-induced release of hydrazine from isoniazid. A possible cause of hepatitis during treatment of tuberculosis with regiments containing isoniazid and rifampin. Am Rev Dis 1986; 133: 1072–1075.

    Google Scholar 

  13. Mitchell JR, Thorgeisson UP, Black M, Timbrell JA, Snodgrass WR, Potter WZ et al. Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydranize metabolites. Clin Parmacol Ther 1975; 18: 70–79.

    Article  CAS  Google Scholar 

  14. Black M, Mitchell JR, Zimmerman HJ, Ishak KG, Elper GR . Isoniazid-associated hepatitis in 114 patients. Gastroenterology 1975; 69: 289–302.

    CAS  PubMed  Google Scholar 

  15. Huang YS, Chern HD, Su WJ, Wu JC, Lai SL, Yang SY et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor of antituberculosis drug-induced hepatitis. Hepatology 2002; 35: 883–889.

    Article  CAS  PubMed  Google Scholar 

  16. Ohno M, Yamaguchi I, Yamamoto I, Fukuda T, Yokota S, Maekura R et al. Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity. Int J Tuber Lung Dis 2000; 4: 256–261.

    CAS  Google Scholar 

  17. Vuilleumier N, Rossier MF, Chiappe A, Deqoumois F, Dayer P, Mermillod B et al. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol 2006; 62: 423–429.

    Article  CAS  PubMed  Google Scholar 

  18. Cho HJ, Koh WJ, Ryu YJ, Ki CS, Nam MH, Kim JW et al. Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis. Tuberculosis 2007; 87: 551–556.

    Article  CAS  PubMed  Google Scholar 

  19. Sunahara S, Urano M, Ogawa M, Yoshida S, Mukoyama H, Kawai K . Genetical aspect of isoniazid metabolism. Jinrui Idengaku Zasshi 1963; 187: 93–111.

    Google Scholar 

  20. Kita T, Tanigawara Y, Chikazawa S, Hatanaka H, Sakeda T, Komada F et al. N-acetyltransferase 2 genotype correlated with isoniazid acetylation in Japanese tuberculous patients. Biol Pharm Bull 2001; 24: 544–549.

    Article  CAS  PubMed  Google Scholar 

  21. Dickinson DS, Bailey WC, Hischowitz BI, Soong SJ, Eidus L, Hodgkin MM . Risk factors for isoniazid (INH)-induced liver dysfunction. J Clin Gastroenterol 1984; 118: 271–279.

    Google Scholar 

  22. Online Mendelian Inheritance in Man, OMIM:. Carboxylesterase-3 (CES-3) John Hopkins University: Baltimore, MD, MIM Number: 605279 http://www.ncbi.nlm.gov/omim/.

  23. The UCSC Genome Bioinformatics Genome Browser: http://genome.ucsc.edu/index.html/org=Human.

  24. Ensembl Genome Browser: http://www.ensembl.org/index.html.

  25. Satoh H, Hosokawa M . Structure, function and regulation of carboxylesterases. Chem Biol Interact 2006; 162: 195–211.

    Article  CAS  PubMed  Google Scholar 

  26. NCBI Browser: http://www.ncbi.nlm.nih.gov/.

  27. EASL International Consensus Conference on Hepatitis C. Paris, 26–28 February 1999, Consensus Statement. European Association for the Study of the Liver. J Hepatol 1999; 30: 956–961.

  28. VISTA Browser: http://pipeline.lbl.gov/cgi-bin/gateway2?bg=hg1.

  29. Hena G, Stephen PM . Conserved noncoding sequences among cultivated cereal genomes identify candidate regulatory sequence elements and patterns of promoter evolution. Plant Cell 2003; 15: 1143–1158.

    Article  Google Scholar 

  30. Rozen S, Skaletsky H . Primer3 on WWW for general users and for biologist programmers. Methods Mol Biol 2000; 132: 365–386.

    CAS  PubMed  Google Scholar 

  31. In Silico PCR http://qsnp.gen.kyushu-u.ac.jp/genome/InSilicoPCR.html.

  32. Brooks-Wilson AR, Kaurah P, Suriano G, Leach S, Snez J, Grehan N et al. Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. J Med Gent 2004; 41: 508–517.

    Article  CAS  Google Scholar 

  33. Barrett J, Fry B, Maller J, Daly M . Haploview: analysis and visualization of LD and haplotype maps. 2005 Available at: http://www.broad.mit.edu/mpg/haploview/).

  34. Shin NR, Yoon SY, Shin JH, Kim YJ, Rhie GE, Kim BS et al. Development of enrichment semi-nested PCR for Clostridium botulinum types A, B, E and F and its application to Korean environmental samples. Mol Cell 2007; 24: 329–337.

    CAS  Google Scholar 

  35. Nickerson DA, Tobe VO, Taylor SL . PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. Nucleic Acids Res 1997; 25: 2745–2751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gordon D, Abajian C, Green P . Consed: a graphical tool for sequence finishing. Genome Res 1998; 8: 195–202.

    Article  CAS  PubMed  Google Scholar 

  37. Benjamini Y, Hochberg Y . Controlling the false discovery rate: a practical and powerful approach to multiple testing. JR Stat Soc B 1995; 57: 289–300.

    Google Scholar 

  38. Lake SL, Lyon H, Tantisira K, Silverman EK, Weiss ST, Laird NM et al. Estimation and tests of haplotype-environment interaction with linkage phase is ambiguous. Hum Hered 2003; 55: 56–65.

    Article  CAS  PubMed  Google Scholar 

  39. Sunyaev S, Ramensky V, Bork P . Towards a structure basis of human non-synonymous single nucleotide polymorphisms. Trends Genet 2000; 16: 198–200. Available at: http://genetics.bwh.harvard.edu/cgibin/pph/polyphen.cgi).

    Article  CAS  PubMed  Google Scholar 

  40. Sunyaev S, Ramensky V, Koch I, Lathe III W, Kondrashov AS, Bork P . Prediction of deleterious human alleles. Hum Mol Genet 2001; 10: 591–597.

    Article  CAS  PubMed  Google Scholar 

  41. Sorting Intolerant From Tolerant http://blocks.fhcrc.org/sift//SIFT.html.

  42. Tanimoto K, Kaneyasu M, Shimokuni T, Hiyama K, Nishiyama M . Human carboxylesterase 1A2 expressed from carboxylesterase 1A1 and 1A2 genes is a potent predictor of CPT-11 cytotoxicity in vitro. Pharmacogenet Genomics 2007; 17: 1–10.

    Article  CAS  PubMed  Google Scholar 

  43. Kamendulis LM, Brzenzinski MR, Pindel EV, Bosron WF, Dean RA . Metabolism of cocaine and heroin is catalyzed by the same human liver carboxylesterases. J Pharmacol Exp Ther 1996; 279: 713–717.

    CAS  PubMed  Google Scholar 

  44. Geshi E, Kimura T, Yoshimura M, Suzuki H, Koba S, Sakai T et al. A single nucleotide polymorphism in the carboxylesterase gene is associated with the responsiveness to imidapril medication and the promoter activity. Hypertens Res 2005; 28: 719–725.

    Article  CAS  PubMed  Google Scholar 

  45. Zhu HJ, Patrick KS, Yuan HJ, Wang JS, Donovan JL, DeVane CL et al. Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. Am J Hum Genet 2008; 82: 1241–1248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kubo T, Kim SR, Sai K, Saito Y, Nakajima T, Matsumoto K et al. Functional characterization of three naturally occurring single nucleotide polymorphisms in the CES2 gene encoding carboxylesterase 2 (HCE-2). Drug Metab Dispos 2005; 33: 1482–1487.

    Article  CAS  PubMed  Google Scholar 

  47. Hussain Z, Kar P, Husain SA . Antituberculosis drug-induced hepatitis: risk factors, prevention and management. Indian J Exp Biol 2003; 41: 1226–1232.

    CAS  PubMed  Google Scholar 

  48. Roy PD, Majumder M, Roy B . Pharmacogenomics of anti-TB drugs-related hepatotoxicity. Pharmacogenomics 2008; 9: 311–321.

    Article  PubMed  Google Scholar 

  49. Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK . Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med 2002; 166: 916–919.

    Article  PubMed  Google Scholar 

  50. Yamada S, Tang M, Richardson K, Halaschek-Wiener J, Chan M, Cook VJ et al. Genetic variation of NAT2 and CTP2E1 and isoniazid hepatotoxicity in a diverse population. Pharmacogenomics 2009; 10: 1433–1445.

    Article  CAS  PubMed  Google Scholar 

  51. Holmes RS, Chan J, Cox LA, Murphy WJ, VandeBerg JL . Opossum carboxylesterases: sequences, phylogeny and evidence for CES gene duplication events predating the marsupial-eutherian common ancestor. BMC Evol Biol 2008; 8: 54.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Gene Card CES http://www.genecards.org/cgi-bin/carddisp.pl?gene=CES.

  53. Balakirev ES, Ayala FJ . Pseudogenes: are they ‘Junk’ or functional DNA? Annu Rev Genet 2003; 37: 123–151.

    Article  CAS  PubMed  Google Scholar 

  54. Yoshimura M, Kimura T, Ishii M, Ishii K, Matsuura T, Geshi E et al. Functional polymorphisms in carboxylesterase 1A2 (CES1A2) gene involves specific protein 1 (Sp1) binding sites. Biochem Biophys Res Commun 2008; 369: 939–942.

    Article  CAS  PubMed  Google Scholar 

  55. Kozak M . Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell 1986; 44: 283–292.

    Article  CAS  PubMed  Google Scholar 

  56. Buckland PR . The importance and identification of regulatory polymorphisms and their mechanism of action. Biochim Biophys Acta 2006; 1762: 17–28.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was funded by a grant from the BC Lung Association to FM and AB-W. AB-W is a senior scholar of the Michael Smith Foundation for Health Research. JH-W was supported in part by an Erwin Schroedinger Fellowship from the Austrian Science Foundation (FWF). VC was supported in part by ‘in it for life’, Vancouver Coastal Health Research Institute. JMFG is a recipient of a Michel Smith Distinguished Scholar Award and a CIHR/BC Lung Scientist Award. SY was supported in part by a Ritsumeikan University International Research Fellowship.

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Correspondence to A Brooks-Wilson.

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Yamada, S., Richardson, K., Tang, M. et al. Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity. Pharmacogenomics J 10, 524–536 (2010). https://doi.org/10.1038/tpj.2010.5

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