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

Luis Jaramillo-Valverde, Kelly S. Levano, David D. Tarazona, Silvia Capristano, Roberto Zegarra-Chapoñan, Cesar Sanchez, Velia M. Yufra-Picardo, Eduardo Tarazona-Santos, Cesar Ugarte-Gil, Heinner Guio

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere1987
JournalMolecular genetics & genomic medicine
Volume10
Issue number8
DOIs
StatePublished - Aug 2022
Externally publishedYes

Keywords

  • CYP2E1
  • NAT2
  • hepatotoxicity
  • tuberculosis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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