Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Aug;10(8):e1987.
doi: 10.1002/mgg3.1987. Epub 2022 Jun 24.

NAT2 and CYP2E1 polymorphisms and antituberculosis drug-induced hepatotoxicity in Peruvian patients

Luis Jaramillo-Valverde  1   2   3 , Kelly S Levano  1 , David D Tarazona  1 , Silvia Capristano  1 , Roberto Zegarra-Chapoñan  1 , Cesar Sanchez  1 , Velia M Yufra-Picardo  4 , Eduardo Tarazona-Santos  2   5 , Cesar Ugarte-Gil  6   7 , Heinner Guio  1   8   9
Affiliations

NAT2 and CYP2E1 polymorphisms and antituberculosis drug-induced hepatotoxicity in Peruvian patients

Luis Jaramillo-Valverde et al. Mol Genet Genomic Med. 2022 Aug.

Abstract

Background: In Peru, 32,970 people were diagnosed with tuberculosis (TB) in 2019. Although TB treatment is effective, 3.4%-13% is associated with significant adverse drug reactions (ADR), considering drug-induced liver injury (DILI) as the most prevalent. Among the first-line anti-TB drugs, isoniazid (INH) is primarily responsible for the occurrence of DILI. INH is metabolized in the liver by the enzymes N-acetyltransferase-2 (NAT2) and Cytochrome P450 2E1 (CYP2E1). Based on the previous studies, we hypothesized that the interactions between slow CYP2E1 genotype and NAT2 slow acetylators will induce DILI in TB patients.

Methods: In this cross-sectional study, all 377 participants completed their anti-TB treatment, and we genotyped SNPs: rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931 for NAT2 and rs3813867 and rs2031920 for CYP2E1.

Results: We found that rapid, intermediate, and slow NAT2 acetylator were 15%, 38%, and 47%, respectively, in the general population. Intermediate NAT2 acetylator is the least prevalent among patients with adverse reactions (p = 0.024). We did not confirm our hypothesis, however, we found that the combination of intermediate NAT2 acetylators and CYP2E1 c1/c1 genotype significantly protected (OR = 0.16; p = 0.049) against the development of DILI in our population.

Conclusion: We propose that the presence of NAT2 intermediate and CYP2E1 c1/c1 genotype could help in therapeutic drug monitoring, and optimize its therapeutic benefits while minimizing its risk for side effects or toxicity.

Keywords: CYP2E1; NAT2; hepatotoxicity; tuberculosis.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflict of interest.

References

    1. Arbex, M. A. , Varella, M. D. C. L. , De Siqueira, H. R. , & De Mello, F. A. F. (2010). Antituberculosis drugs: Drug interactions, adverse effects, and use in special situations. Part 1: First‐line drugs. Jornal Brasileiro de Pneumologia, 36(5), 626–640. 10.1590/s1806-37132010000500016 - DOI - PubMed
    1. Bisso‐Machado, R. , Ramallo, V. , Paixão‐Côrtes, V. R. , Acuña‐Alonzo, V. , Demarchi, D. A. , Sandoval, J. R. S. , Granara, A. A. S. , Salzano, F. M. , Hünemeier, T. , & Bortolini, M. C. (2016). NAT2 gene diversity and its evolutionary trajectory in the Americas. Pharmacogenomics Journal, 16(6), 559–565. 10.1038/tpj.2015.72 - DOI - PubMed
    1. Cai, Y. , Yi, J. , Zhou, C. , & Shen, X. (2012). Pharmacogenetic study of drug‐Metabolising enzyme polymorphisms on the risk of anti‐tuberculosis drug‐induced liver injury: A meta‐analysis. PLoS One, 7(10), e47769. 10.1371/journal.pone.0047769 - DOI - PMC - PubMed
    1. Cascorbi, I. , Drakoulis, N. , Brockmoller, J. , Maurer, A. , Sperling, K. , & Roots, I. (1995). Arylamine N‐acetyltransferase (NAT2) mutations and their allelic linkage in unrelated Caucasian individuals: Correlation with phenotypic activity. American Journal of Human Genetics, 57(3), 581 /pmc/articles/PMC1801274/?report=abstract. - PMC - PubMed
    1. Cho, H.‐J. , Koh, W.‐J. , Ryu, Y.‐J. , Ki, C.‐S. , Nam, M.‐H. , Kim, J.‐W. , & Lee, S.‐Y. (2007). Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug‐induced hepatotoxicity in Korean patients with pulmonary tuberculosis. Tuberculosis, 87(6), 551–556. 10.1016/j.tube.2007.05.012 - DOI - PubMed

Publication types

MeSH terms