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Comparison between acetylator phenotype and genotype polymorphism of n-acetyltransferase-2 in tuberculosis patients

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Abstract

Background

Isoniazid (INH) is one of the most important drugs of antitubercular treatment regime, and in some cases it causes hepatotoxicity. It is metabolized by hepatic N-acetyltransferase-2 (NAT2).

Aim

To compare whether both methods, i.e., genotype NAT2 and phenotype test of measuring serum INH levels, are useful to identify acetylator status of patients on antitubercular treatment (ATT).

Methods

A total of 251 tuberculosis (TB) patients on standard treatment were followed up to 6 months for this study. NAT2 genotype was assessed by PCR with restriction fragment length polymorphism (RFLP) whereas serum INH levels were measured by fluorometry.

Results

Of the 251 patients, 50 (19.9%) developed ATT-induced hepatotoxicity. By phenotypic estimation, in the hepatotoxicity group, 17/50 (34%) were slow acetylators whereas 33/50 (66%) were fast acetylators. Genotypically, 19/50 (38%) were slow acetylators and 31/50 (62%) fast acetylators. By phenotypic analysis, in non-hepatotoxicity group, 46/201 (22.9%) were slow acetylators and 155/201 (77.1%) fast acetylators. By genotypic analysis, 30/201 (14.9%) were slow acetylators and 171/201 (85%) fast acetylators. Overall, slow acetylators (25.1%) measured phenotypically were not significantly different from slow acetylators (19.5%) measured genotypically.

Conclusion

This study suggests that the acetylator status of TB patients can be detected by phenotypic method as efficaciously as by genotypic method. Therefore, phenotypic method can replace genotypic method to determine acetylating status as phenotypic method is simple and inexpensive.

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References

  1. Lee WM. Drug-induced hepatotoxicity. N Engl J Med 1995;333:11–18

    Article  Google Scholar 

  2. Hwang SJ, Lee CN, Yen FS, et al. A prospective clinical study of isoniazid–rifampcin–pyrazinamide induced liver injury in an area endemic for hepatitis. Br J Gastroenterol Hepatol 1997;12:87–92

    Article  CAS  Google Scholar 

  3. Tariq S, Khan TS, Malik S, Anwar MS, Rashid A. Frequency of anti-tuberculous therapy-induced hepaptotoxicity in patients and their outcome. J Ayub Med Coll Abbottabad 2009;21:50–52

    PubMed  Google Scholar 

  4. Huang YS, Chern HD, Su WJ, et al. CytochromeP4502E1 genotype susceptibility to anti-tuberculosis drug induced hepatitis. Herpetology 2003;37:924–930

    CAS  Google Scholar 

  5. Tsuchida S, Sato K. Glutathione transferases and cancer. Crit Rev Biochem Mol Biol 1992;27:337–384

    Article  PubMed  CAS  Google Scholar 

  6. Mitchell JR, Zimmerman HJ, Ishak KG, et al. Isoniazid liver injury: clinical spectrum, pathology and probable pathogenesis. Ann Intern Med 1976;84:181–192

    PubMed  CAS  Google Scholar 

  7. Farrell GC. Drug-induced acute hepatitis. In Farrell GC, editor. Drug-induced liver disease. Churchill Livingstone: Edinburgh; 1994. 247–99.

    Google Scholar 

  8. Ryan DE, Ramanathan L, Iida S, et al. Characterization of a major form of rat hepatic microsomal cytochrome P-450 induced by isoniazid. J Bio Chem 1985;260:6385–6393

    CAS  Google Scholar 

  9. Tao L, Xiang YB, Wang R, et al. Environmental tobacco smoke in relation to bladder cancer risk—the Shanghai bladder cancer study. Cancer Epidemiol Biomarkers Prev 2010;19:3087–3095

    Article  PubMed  CAS  Google Scholar 

  10. Rabstein S, Brüning T, Harth V, et al. N-acetyltransferase 2, exposure to aromatic and heterocyclic amines, and receptor-defined breast cancer. Eur J Cancer Prev 2010;19:100–109

    Article  PubMed  CAS  Google Scholar 

  11. Sun F, Chen Y, Xiang Y, Zhan S. Drug-metabolizing enzyme polymorphism and predisposition to anti-tuberculosis drug induced liver injury: a meta-analysis. Int J Tuberc lung Dis 2008;12:994–1002

    PubMed  CAS  Google Scholar 

  12. Huang YS, Chern HD, Su WJ, et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor of anti-tuberculosis drug-induced hepatitis. Hepatology 2002;35:883–889

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. Benichou C. Criteria of drug induced liver disorders: reform of international consensus meeting. J Hepatol 1990;11:272–276

    Article  PubMed  CAS  Google Scholar 

  15. Sud K, Muthukumar T, Singh B, et al. Isoniazid does not affect bioavailability of cyclosporine in renal transplant recipients. Methods Find Exp Clin Pharmacol 2000;22:647–649

    Article  PubMed  CAS  Google Scholar 

  16. Scott EM, Wright RC. Fluorimetric determination of isonicotinic acid hydrazide in serum. J Lab Clin Med 1967;70:353–360

    Google Scholar 

  17. Neughaur S, BabaT Watanabe T, Ishizaki T, Kurokawa K. An early risk marker for diabetic nephropathy in Japanese type 2 diabetic patients. Diabetic Med 1994;11:783–788

    Article  Google Scholar 

  18. Suzuki H, Morris JS, Li Y, et al. Interaction of the cytochrome P4501A2, SULT1A1 and NAT gene polymorphisms with smoking and dietary mutagen intake in modification of the risk of pancreatic cancer. Carcinogenesis 2008;29:1184–1191

    Article  PubMed  CAS  Google Scholar 

  19. Rana SV, Pal R, Vaiphei K, Ola RP, Singh K. Hepatoprotection by carotenoids in isoniazid-rifampicin induced hepatic injury in rats. Biochem Cell Biol 2010;88:819–834

    Article  PubMed  CAS  Google Scholar 

  20. Evans DAP. N-acetyltransferase. Pharmacol Ther 1989;42:157–234

    Article  Google Scholar 

  21. Mahmood K, Hussain A, Jairmani KL, et al. Hepatotoxicity with anti-tuberculosis drugs: the risk factors. Pak J Med Sci 2007;23:33–38

    Google Scholar 

  22. Ohno M, Yamaguchi I, Yamamoto I, et al. Slow N-acetyltransferase 2 genotype affects the incidence of INH and RMP induced hepatotoxicity. Intl J Tuberc Lung Dis 2000;4:256–261

    CAS  Google Scholar 

  23. Doll Ma, Fretland AJ, Deitz AC, Hein W. Determination of human NAT2 acetylator genotype by restriction fragment length polymorphism and allele- specific amplification. Anal Biochem 1995;231:413–418

    Article  PubMed  CAS  Google Scholar 

  24. Freguson RJ, Doll MA, Rustan TD, Gray K, Hein DW. Cloning, expression and functional characterization of two mutant (NAT2–191and NAT2–341/803) and wild-type human polymorphic N-acetyltransferase (NAT2) alleles. Drug Metabol Dispos 1994;22:371–376

    Google Scholar 

  25. Parthasarthy R, Sarma GR, Janardhanam B, et al. Hepatic toxicity in south Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide. Tubercule 1986;67:99–108

    Article  Google Scholar 

  26. Gurumurthi P, Kirshnamurthy MS, Nazareth O, et al. Lack of relationship between hepatic toxicity and acetylator phenotype in three thousand south Indian patients during treatment with isoniazid for tuberculosis. Am Rev Respir Dis 1984;129:58–61

    Google Scholar 

  27. Vatsis KP, Weber WW, Bel DA, et al. Nomenclature for N-acetyltransferase genetic polymorphism of cytochrome P4502E1 in Swedish population. Relationship to incidence of lung cancer. Pharmacogenesis 1995;5:1–20

    Article  CAS  Google Scholar 

  28. Bose PD, Sarma MP, Medhi S, et al. Role of polymorphic N-acetyl transferase 2 and cytochrome P4502E1 gene in antituberculosis treatment-induced hepatitis. J Gastroenterology and Hepatology 2011;26:312–318

    Article  CAS  Google Scholar 

  29. Díaz-Molina R, Cornejo-Bravo JM, Ramos-Ibarra MA. Genotypye and phenotype of NAT2 and the occurrence of adverse drug reaction in Mexican individuals to an isonizid-based prophylactic chemotherapy for tuberculosis. Mol Med Rep 2008;1:875–879

    Google Scholar 

  30. Singh N, Dubey S, Chinnaraj S, Golani A, Maitra A. Study of NAT2 gene polymorphisms in an Indian population: association with plasma isoniazid concentration in a cohort of tuberculosis patients. Mol Diag Ther 2009;13:49–58

    CAS  Google Scholar 

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Acknowledgements

Financial assistance by ICMR to carry out this research work is acknowledged.

Conflict of interest

Nothing is to disclose.

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Authors and Affiliations

  1. Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    S. V. Rana, R. P. Ola, Sanjeev K. Sharma, S. K. Sinha & K. Singh

  2. Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    S. K. Arora

  3. Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    P. Pandhi

  4. House # 137, Sector 15-A, Chandigarh, 160015, India

    S. V. Rana

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  1. S. V. Rana
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  2. R. P. Ola
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  3. Sanjeev K. Sharma
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  4. S. K. Arora
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  5. S. K. Sinha
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  6. P. Pandhi
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  7. K. Singh
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Correspondence to S. V. Rana.

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Rana, S.V., Ola, R.P., Sharma, S.K. et al. Comparison between acetylator phenotype and genotype polymorphism of n-acetyltransferase-2 in tuberculosis patients. Hepatol Int 6, 397–402 (2012). https://doi.org/10.1007/s12072-011-9309-4

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  • DOI: https://doi.org/10.1007/s12072-011-9309-4

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