European Journal of Clinical Pharmacology

, Volume 62, Issue 6, pp 423–429 | Cite as

CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis

  • Nicolas VuilleumierEmail author
  • Michel F. Rossier
  • Alberto Chiappe
  • Florence Degoumois
  • Pierre Dayer
  • Bernadette Mermillod
  • Laurent Nicod
  • Jules Desmeules
  • Denis Hochstrasser



To determine whether pharmacogenetic tests such as N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) genotyping are useful in identifying patients prone to antituberculosis drug-induced hepatotoxicity in a cosmopolite population.


In a prospective study we genotyped 89 patients treated with isoniazid (INH) for latent tuberculosis. INH-induced hepatitis (INH-H) or elevated liver enzymes including hepatitis (INH-ELE) was diagnosed based on the clinical diagnostic scale (CDS) designed for routine clinical practice. NAT2 genotypes were assessed by fluorescence resonance energy transfer probe after PCR analysis, and CYP2E1 genotypes were determined by PCR with restriction fragment length polymorphism analysis.


Twenty-six patients (29%) had INH-ELE, while eight (9%) presented with INH-H leading to INH treatment interruption. We report no significant influence of NAT2 polymorphism, but we did find a significant association between the CYP2E1 *1A/*1A genotype and INH-ELE (OR: 3.4; 95% CI:1.1-12; p=0.02) and a non significant trend for INH-H (OR: 5.9; 95% CI: 0.69–270; p=0.13) compared with other CYP2E1 genotypes. This test for predicting INH-ELE had a positive predictive value (PPV) of 39% (95% CI: 26–54%) and a negative predictive value (NPV) of 84% (95% CI: 69–94%).


The genotyping of CYP2E1 polymorphisms may be a useful predictive tool in the common setting of a highly heterogeneous population for predicting isoniazid-induced hepatic toxicity. Larger prospective randomized trials are needed to confirm these results.


Cosmopolite population CYP2E1 TaqI polymorphism Isoniazid-induced hepatitis NAT2 genotype Negative predictive value Positive predictive value 



Alanine transaminase


Aspartate transaminase


Clinical diagnostic scale


Confidence interval


False negative


False positive


Intermediate acetylator




Isoniazid-induced elevated liver enzymes


Isoniazid-induced hepatitis


N-acetyltransferase type 2


Negative predictive value


Odds ratio


Positive predictive value


Rapid acetylator


Restriction fragment length polymorphism


Slow acetylator






True negative


True positive



Upper reference limit



We are indebted to Dr, J.-D. Graf for the resolution of Hardy-Weinberg equation, to Dr. V. Rollason for the revision of the manuscript, to the nurses of the Anti-tuberculosis Centre and the staff of the Central Laboratory of Chemistry for their technical support. This experiment complies with the current laws of Switzerland in which it was performed inclusive of ethics approval.


  1. 1.
    Dye C (1999) Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 282:677–686PubMedCrossRefGoogle Scholar
  2. 2.
    Durant F, Jebrak G, Pessayre D, Fournier M, Bernau J (1996) Hepatotoxicity of antitubercular treatments. Rationale for monitoring liver status. Drug Saf 16:394–405Google Scholar
  3. 3.
    Martinjak-Dvorsek I, Gorjup V, Horvat M, Noc M (2000) Acute isoniazid neurotoxicity during preventive therapy. Crit Care Med 28:567–568PubMedCrossRefGoogle Scholar
  4. 4.
    Watkins RC, Hambrick EL, Benjamin G, Chavda SN (1990) Isoniazid toxicity presenting as seizures and metabolic acidosis. J Natl Med Assoc 82:57–64PubMedGoogle Scholar
  5. 5.
    Schaberg T, Rebhan K, Lode H (1996) Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis. Eur Respir J 9:2026–2030PubMedCrossRefGoogle Scholar
  6. 6.
    Morant J, Ruppaner H (2003) Compendium Suisse des Médicaments, 24th edn. Documed, GenevaGoogle Scholar
  7. 7.
    Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D (2003) Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 167:1472–1477PubMedCrossRefGoogle Scholar
  8. 8.
    Steele MA, Burk RF, DesPrez RM (1991) Toxic hepatitis with isoniazid and rifampin a meta-analysis. Chest 99:465–471PubMedCrossRefGoogle Scholar
  9. 9.
    Saram GR, Imanuel C, Kailasam S, Narayana ASL, Venkatesan P (1986) 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 133:1072–1075Google Scholar
  10. 10.
    Mitchell JR, Thorgeisson UP, Black M et al (1975) Increased incidence of isoniazid hepatitis in rapid acetylators : possible relation to hydralazine metabolites. Clin Pharmacol Ther 18:70–79PubMedGoogle Scholar
  11. 11.
    Black M, Mitchell JR, Zimmerman HJ, Ishak KG, Elper GR (1975) Isoniazid-associated hepatitis in 114 patients. Gastroenterology 69:289–302PubMedGoogle Scholar
  12. 12.
    Mitchell JR, Zimmerman HJ, Ishak KG, Thorgeisson UP, Timbrell JA, Snodgrass WR, Nelson SD (1976) Isoniazid Liver injury: clinical spectrum, pathology and probable pathogenesis. Ann Intern Med 84:181–192PubMedGoogle Scholar
  13. 13.
    Spielberg SP (1996) N-acetyltransferases: Pharmacogenetics and clinical consequences of polymorphism drug metabolism. J Pharmacokinet Biopharm 509–19Google Scholar
  14. 14.
    Singh J, Garg PK, Thakur VS, Tandon RK (1995) Anti-tubercular treatment induced hepatotoxicity: does acetylator status matter? Indian J Physiol Pharmacol 39:43–46PubMedGoogle Scholar
  15. 15.
    Ryan DE, Ramanathan L, Iilda S, Thomas PE, Hainu M, Shively JE, Lieber CS et al (1985) Characterisation of a major form of rat hepatic microsomal cytochrome P-450 induced by isoniazid. J Biol Chem 260:6385–6393PubMedGoogle Scholar
  16. 16.
    Cascorbi I, Drakoulis N, Brockmöller J, Maurer A, Sperling K, Roots I (1995) Arylamine N-acetyl transferase (NAT2) mutations and their allelic linkage in unrelated Caucasian individual: correlation with phenotypic activity. Am J Hum Gen 57:581–592Google Scholar
  17. 17.
    Parkin PD, VandenPlas S, Botha FJH (1997) Trimodality of isoniazid elimination. Phenotype and genotype in patients with tuberculosis. Am J Respir Crit Care Med 155:1717–1722PubMedGoogle Scholar
  18. 18.
    Smith CAD, Wadelius M, Gough AC, Harrison DJ, Wolf CR, Rane A (1997) A simplified assay for the arylamine N-acetyltransferase 2 polymorphism validated by phenotyping with isoniazid. J Med Genet 34:758–760PubMedCrossRefGoogle Scholar
  19. 19.
    Ohno M, Yamaguchi I, Yamamoto I, Fukuda T, Yokota S, Maekura R, Ito M, Yamamoto Y, et al (2000) Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity. Int J Tuberc Lung Dis 4:256–261PubMedGoogle Scholar
  20. 20.
    Gurumutry P, Krishnamurthy MS, Nasareth O (1984) Parthasarthy R, Samara GR, Somasundaram PR, Tripathy SP et al (1984) Lack of relationship between hepatotoxicity and acetylator phenotype in three thousand south Indian patients during treatment with isoniazid for tuberculosis. Am Rev Respir Dis 129:58–61Google Scholar
  21. 21.
    Dickinson DS, Bailey WC, Hirschowitz BI, Soong SJ, Eidus L, Hodgkin MM (1981) Risk factors for isoniazid (INH)-induced liver dysfunction. J Clin Gastroenterol 3:271–279PubMedCrossRefGoogle Scholar
  22. 22.
    Lieber CS (1997) Cytochrome P-4502E1: its physiological and pathological role. Physiol Rev 77:517–544PubMedGoogle Scholar
  23. 23.
    Tanaka E, Terarda M ,Misawa S (2000) Cytochrome P4502E1.Its clinical and toxicological role. J Clin Pharm Ther 25:165–175PubMedCrossRefGoogle Scholar
  24. 24.
    Lucas D, Ferrara R, Gonzales E, Albores A, Manno M, Berthou F (2001) Cytochrome CYP2E1 phenotyping and genotyping in the evaluation of health risks from exposure to polluted environments. Toxicol Lett 124:71–81PubMedCrossRefGoogle Scholar
  25. 25.
    Wong NACS, Rae F, Simpson KJ, Murray GD, Harrison DJ (2000) Genetic polymorphism of cytochrome p4502E1 and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a white population: a study and literature review, including meta analysis. J Clin Pathol Mol Pathol 53:88–93CrossRefGoogle Scholar
  26. 26.
    Haufroid V, Buchet JP, Gardinal S, Lison D (2002) Cytochrome P4502E1 phenotyping by the measurement of the chlorzoxazone metabolic ratio: assessment of its usefulness in workers exposed to styrene. Int Arch Occup Environ Health 75:453–458CrossRefGoogle Scholar
  27. 27.
    Huang YS, Chern HD, Su WJ, Wu JC, Lai SL, Yang SY, Chang FY et al (2003) Cytochrome P450 2E1 genotype and the susceptibility to antituberculous drug-induced hepatitis. Hepatology 37:924–930PubMedCrossRefGoogle Scholar
  28. 28.
    Huang YS, Chern HD, Su WJ, Wu JC, Lai SL, Yang SY, Chang FY et al (2002) Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology 35(4):883–889PubMedCrossRefGoogle Scholar
  29. 29.
    American Thoracic Society (2000) Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Recommendation Rep 49:1–51Google Scholar
  30. 30.
    Kopanoff DE, Snider DE, Caras GJ (1978) Isoniazid related hepatitis : A US public health service cooperative surveillance study. Am Rev Resp Dis 117:991–1001PubMedGoogle Scholar
  31. 31.
    Ozick LA, Jacob L, Comer GM, Lee TP, Ben-Zvi J, Donelson SS, Felton CP (1995) Hepatotoxicity from isoniazid and rifampin in inner-city AIDS patients. Am J Gastroenterol 90:1978–1980PubMedGoogle Scholar
  32. 32.
    Guruprasad P. Aithal GP, Rawlins MD, Day CP (2000) Clinical diagnostic scale: a useful tool in the evaluation of suspected hepatotoxic adverse drug reactions. J Hepatol 33:949–952CrossRefGoogle Scholar
  33. 33.
    Guo SW, Thompson EA (1992) Performing the exact test of Hardy-Weinberg proportion for multiple alleles. Biometrics 48:361–372PubMedCrossRefGoogle Scholar
  34. 34.
    Xie HG, Xu ZH, Ou-Yang DS, Shu Y, Yang DL, Wang JS, Yan XD et al (1997) Metaanalysis of phenotype and genotype of NAT2 deficiency in Chinese population. Pharmacogenetics 7:503–514PubMedCrossRefGoogle Scholar
  35. 35.
    Cascorbi I, Roots I (1999) Pitfalls in N-acetyltransferase-2 genotyping. Pharmcogenetics 9:123–127CrossRefGoogle Scholar
  36. 36.
    Aynacioglu AS, Cascorbi I, Mrozikiewics PM, Roots I (1997) Arylamine N-acetyltransferase (NAT2) genotypes in a Turkish population. Pharmacogenetics 7:327–331PubMedCrossRefGoogle Scholar
  37. 37.
    Mandell GL, Petri WA (1996) Antimicrobial agents. In: Goodman G (eds) The pharmacological basis of therapeutics 9th edn. Donnelley and Sons, Chicago, Ill., pp 1155–1174Google Scholar
  38. 38.
    Branch RA, Adedoyin A, Frye RF, Wilson JW, Romkes M (2000) In vivo modulation of CYP enzymes by quinidine and rifampin. Clin Pharmacol Ther 68:401–411PubMedCrossRefGoogle Scholar
  39. 39.
    Zand R, Nelson SD, Slaterry JT, Thummel KE, Kalhorn TF, Adams SP, Wright JM (1993) Inhibition and induction of cytochrome P4502E1-catalysed oxidation by isoniazid in humans. Clin Pharmacol Ther 54:142–149PubMedCrossRefGoogle Scholar
  40. 40.
    Hwang SJ, Wu JC, Lee CN, Yen FS, Lu CJ, Lin TP, Lee SD (1997) A prospective clinical study of isoniazid-rifampicin-pyrazinamid-induced liver injury in an area endemic for hepatitis B. J Gastroenterol Hepatol 12:87–91PubMedCrossRefGoogle Scholar
  41. 41.
    Wong WM, Wu PC, Yuen MF, Cheng CC, Yew WW, Wong PC, Tam CM et al (2000) Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology 31:201–206PubMedCrossRefGoogle Scholar
  42. 42.
    Yamamoto T, Suou T, Hirayama C (1986) Elevated serum amino-transferase induced by isoniazid in relation to isoniazid acetylator phenotype. Hepatology 6:295–298PubMedCrossRefGoogle Scholar
  43. 43.
    American Thoracic Society (1994) Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Resp Crit Care Med 149:1359–1374Google Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Nicolas Vuilleumier
    • 1
    Email author
  • Michel F. Rossier
    • 1
    • 5
  • Alberto Chiappe
    • 1
  • Florence Degoumois
    • 1
  • Pierre Dayer
    • 2
  • Bernadette Mermillod
    • 3
  • Laurent Nicod
    • 4
  • Jules Desmeules
    • 2
  • Denis Hochstrasser
    • 1
  1. 1.Central Clinical Chemistry Laboratory, Department of Clinical PathologyGeneva University HospitalGeneva 14Switzerland
  2. 2.Clinical Pharmacology and ToxicologyGeneva University HospitalGeneva 14Switzerland
  3. 3.Service of Medical InformaticsGeneva University HospitalGeneva 14Switzerland
  4. 4.Service of PneumologyGeneva University HospitalGeneva 14Switzerland
  5. 5.Service of Endocrinology and DiabetologyGeneva University HospitalGeneva 14Switzerland

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