TY - JOUR
T1 - NAT2 and CYP2E1 polymorphisms and antituberculosis drug-induced hepatotoxicity in Peruvian patients
AU - Jaramillo-Valverde, Luis
AU - Levano, Kelly S.
AU - Tarazona, David D.
AU - Capristano, Silvia
AU - Zegarra-Chapoñan, Roberto
AU - Sanchez, Cesar
AU - Yufra-Picardo, Velia M.
AU - Tarazona-Santos, Eduardo
AU - Ugarte-Gil, Cesar
AU - Guio, Heinner
N1 - Funding Information:
LJ‐V is a doctoral student of the Epidemiological Research program at the Universidad Peruana Cayetano Heredia with a grant EF033‐235‐2015 from FONDECYT/CIENCIACTIVA and supported by the training grant D43 TW007393 from the Fogarty International Center of the US National Institutes of Health. The original study was supported by the Instituto Nacional de Salud, Lima, Perú.
Publisher Copyright:
© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
KW - CYP2E1
KW - hepatotoxicity
KW - NAT2
KW - tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=85132577210&partnerID=8YFLogxK
U2 - 10.1002/mgg3.1987
DO - 10.1002/mgg3.1987
M3 - Artículo
C2 - 35751408
AN - SCOPUS:85132577210
SN - 2324-9269
VL - 10
JO - Molecular Genetics and Genomic Medicine
JF - Molecular Genetics and Genomic Medicine
IS - 8
M1 - e1987
ER -