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Association of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To determine the frequency of N-acetyltransferase 2 (NAT2) polymorphisms, the NAT2 acetylation profile and its relation to the incidence of gastrointestinal adverse drug reactions (ADRs), anti-tuberculosis (TB) drug-induced hepatotoxicity, and the clinical risk factors for hepatotoxicity in a population from Brazil.

Methods

Two hundred and fifty-four Brazilian TB patients using isoniazid (INH), rifampicin (RMP), and pirazinamide (PZA) were tested in a prospective cohort study. NAT2 genotyping was performed by direct PCR sequencing. The association between gastrointestinal ADRs/hepatotoxicity and the NAT2 profile genotype was evaluated by univariate analysis and multiple logistic regression.

Results

Of the 254 patients analyzed, 69 (27.2%) were slow acetylators and 185 (72.8%) were fast acetylators. Sixty-five (25.6%) patients were human immunodeficiency virus (HIV)-positive. Thirty-three (13%) and 14 (5.5%) patients developed gastrointestinal ADR and hepatotoxicity, respectively. Of the 14 hepatotoxicity patients, nine (64.3%) were slow acetylators and five (35.7%) were fast acetylators. Sex, age, presence of hepatitis C virus, alcohol abuse, and baseline aminotransferases were not found to be risk factors for hepatotoxicity. However, logistic regression analysis revealed that slow acetylator status and the presence of HIV (p < 0.05) were independent risk factors for hepatotoxicity.

Conclusions

Our findings show that HIV-positive patients that have the slow acetylation profile are significantly associated with a higher risk of developing hepatotoxicity due to anti-TB drugs.

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Acknowledgments

The authors wish to thank trial participants for their consent and participation in the study, and we also thank the staff of the outpatient Department and Research and Knowledge Department from Sanatorio Partenon Hospital for their assistance. This work was supported by National Council for Research (CNPq), Laboratório Exame, Novo Hamburgo, RS, and PADCT/ FEPPS. Adalberto R. Santos is supported by CNPq Grant number 308786/2005-0. We declare that the experiments comply with the Brazilian current laws.

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Authors and Affiliations

  1. Centro de Desenvolvimento Científico e Tecnológico da Fundação Estadual de Produção e Pesquisa em Saúde, 5400, Avenida Ipiranga, Porto Alegre, RS, 90610-000, Brazil

    L. G. Possuelo, T. C. de Brito, A. W. Ribeiro, P. I. Cafrune, T. S. Gregianini & M. L. R. Rossetti

  2. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, 2600, Ramiro Barcelos, Porto Alegre, RS, 90035-003, Brazil

    L. G. Possuelo & P. I. Cafrune

  3. Programa de Pós-Graduação em Genética e Toxicologia Aplicada, Universidade Luterana do Brasil, 8001, Avenida Farroupilha, São José (Canoas), RS, 92425-900, Brasil

    J. A. Castelan & M. L. R. Rossetti

  4. Laboratório Exame, 1040, Joaquim Nabuco, Novo Hamburgo, RS, 93310-002, Brazil

    J. A. Castelan

  5. Hospital Sanatório Partenon, 3722, Bento Gonçalves, Porto Alegre, RS, 90650-001, Brazil

    P. D. Picon

  6. Laboratório de Biologia Molecular Aplicada a Micobactérias, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, IOC/Fiocruz, 4365, Avenida Brazil, Manguinhos, Rio de Janeiro, 21040-900, Brazil

    A. R. Santos

  7. Laboratório de Genética Humana, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, IOC/Fiocruz, 4365, Avenida Brazil, Manguinhos, Rio de Janeiro, 21040-900, Brazil

    R. L. F. Teixeira

  8. Departamento de Genética, IB, Universidade Federal do Rio Grande do Sul, 9500, Avenida Bento Gonçalves, Prédio 43323, Porto Alegre, RS, 91501-970, Brazil

    M. H. Hutz

  9. Departamento de Biologia Molecular e Biotecnologia, IB, and Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, 9500, Avenida Bento Gonçalves, Prédio 43421, Porto Alegre, RS, 91501-70, Brazil

    A. Zaha

Authors
  1. L. G. Possuelo
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  2. J. A. Castelan
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  3. T. C. de Brito
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  4. A. W. Ribeiro
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  5. P. I. Cafrune
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  6. P. D. Picon
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  7. A. R. Santos
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  8. R. L. F. Teixeira
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  9. T. S. Gregianini
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  10. M. H. Hutz
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  11. M. L. R. Rossetti
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  12. A. Zaha
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Corresponding author

Correspondence to A. Zaha.

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Supplementary Table 1

Analysis of medication type and drug groups in use by patients studied (DOC 62 KB)

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Possuelo, L.G., Castelan, J.A., de Brito, T.C. et al. Association of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil. Eur J Clin Pharmacol 64, 673–681 (2008). https://doi.org/10.1007/s00228-008-0484-8

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  • DOI: https://doi.org/10.1007/s00228-008-0484-8

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