Laboratorio de Biotecnología y Biología Molecular, Instituto Nacional de Salud, Lima, Peru.
School of Public Health and Administration, Universidad Peruana Cayetano Heredia, Lima, Peru.
Mol Genet Genomic Med. 2022 Aug;10(8):e1987. doi: 10.1002/mgg3.1987. Epub 2022 Jun 24.
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.
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.
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.
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.
2019 年，秘鲁有 32970 人被诊断患有结核病（TB）。尽管 TB 治疗效果显著，但仍有 3.4%-13%的患者出现严重药物不良反应（ADR），其中以药物性肝损伤（DILI）最为常见。在一线抗 TB 药物中，异烟肼（INH）主要导致 DILI 的发生。INH 在肝脏中被 N-乙酰转移酶-2（NAT2）和细胞色素 P450 2E1（CYP2E1）等酶代谢。基于以往的研究，我们假设慢 CYP2E1 基因型与 NAT2 慢乙酰化酶之间的相互作用会导致 TB 患者发生 DILI。
在这项横断面研究中，所有 377 名参与者均完成了抗 TB 治疗，我们对 NAT2 的 SNP：rs1041983、rs1801280、rs1799929、rs1799930、rs1208 和 rs1799931 以及 CYP2E1 的 rs3813867 和 rs2031920 进行了基因分型。
我们发现，在一般人群中，快速、中间和慢速 NAT2 乙酰化酶的比例分别为 15%、38%和 47%。中间 NAT2 乙酰化酶在有不良反应的患者中最不常见（p=0.024）。然而，我们没有证实我们的假设，我们发现中间 NAT2 乙酰化酶和 CYP2E1 c1/c1 基因型的组合显著保护（OR=0.16；p=0.049）我们人群中 DILI 的发生。
我们提出，NAT2 中间和 CYP2E1 c1/c1 基因型的存在可以帮助进行治疗药物监测，并在优化其治疗效益的同时最大程度地降低副作用或毒性的风险。
