Homozygotes NAT25B slow acetylators are highly associated with hepatotoxicity induced by anti-tuberculosis drugs

Distinct N-acetyltransferase 2 (NAT2) slow acetylators genotypes have been associated with a higher risk to develop anti-tuberculosis drug-induced hepatotoxicity (DIH). However, studies have not pointed the relevance of different acetylation phenotypes presented by homozygotes and compound heterozyg...

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Published inMemórias do Instituto Oswaldo Cruz Vol. 117; p. e210328
Main Authors El-Jaick, Kenia Balbi, Ribeiro-Alves, Marcelo, Soares, Marcos Vinícius Guimarães, Araujo, Gabriela Eduardo França de, Pereira, Gabriel Rodrigues Coutinho, Rolla, Valeria Cavalcanti, Mesquita, Joelma Freire De, De Castro, Liane
Format Journal Article
LanguageEnglish
Portuguese
Published Brazil Instituto Oswaldo Cruz, Ministério da Saúde 01.01.2022
Subjects
PARASITOLOGY
TROPICAL MEDICINE
precision medicine
liver injury
chemically induced liver toxicity
arylamine N acetyltransferase 2
rs1801280
toxic hepatitis
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Summary:Distinct N-acetyltransferase 2 (NAT2) slow acetylators genotypes have been associated with a higher risk to develop anti-tuberculosis drug-induced hepatotoxicity (DIH). However, studies have not pointed the relevance of different acetylation phenotypes presented by homozygotes and compound heterozygotes slow acetylators on a clinical basis. This study aimed to investigate the association between NAT2 genotypes and the risk of developing DIH in Brazilian patients undergoing tuberculosis treatment, focusing on the discrimination of homozygotes and compound heterozygotes slow acetylators. The frequency of NAT2 genotypes was analysed by DNA sequencing in 162 patients undergoing tuberculosis therapy. The mutation analyses revealed 15 variants, plus two new NAT2 mutations, that computational simulations predicted to cause structural perturbations in the protein. The multivariate statistical analysis revealed that carriers of NAT2*5/*5 slow acetylator genotype presented a higher risk of developing anti-tuberculosis DIH, on a clinical basis, when compared to the compound heterozygotes presenting NAT2*5 and any other slow acetylator haplotype [aOR 4.97, 95% confidence interval (CI) 1.47-16.82, p = 0.01]. These findings suggest that patients with TB diagnosis who present the NAT2*5B/*5B genotype should be properly identified and more carefully monitored until treatment outcome in order to prevent the occurrence of anti-tuberculosis DIH.
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KBE, MRA, GRCP, MVGS, GEFA, JFDM, VCR and LDC performed research, collected, and analysed data presented in this manuscript, review and edit the manuscript; KBE, MRA, JFDM, GRCP and LDC wrote the manuscript; KBE and LDC conceived and designed the research. The authors declare that there are no competing interests associated with the manuscript.
ISSN:0074-0276
1678-8060
1678-8060
DOI:10.1590/0074-02760210328