Association of Cytochrome P450 2E1 and N-Acetyltransferase 2 Genotypes with Serum Isoniazid Level and Anti-Tuberculosis Drug-Induced Hepatotoxicity: A Cross-Sectional Study.

IF 1.6 Q2 MEDICINE, GENERAL & INTERNAL Iranian Journal of Medical Sciences Pub Date : 2023-09-01 DOI:10.30476/ijms.2023.96145.2765
Nasir Pourmohamadi, Mihan Pour Abdollah Toutkaboni, Nasim Hayati Roodbari, Payam Tabarsi, Shadi Baniasadi
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Abstract

Background: Anti-tuberculosis drug-induced hepatotoxicity can result from genetic polymorphism of the isoniazid (INH) metabolizing enzyme. This study aimed to determine the effect of genetic polymorphism of N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) genes on serum isoniazid level and drug-induced hepatotoxicity.

Methods: A cross-sectional study was conducted on 120 patients (with and without hepatotoxicity) with pulmonary tuberculosis from June 2019 to April 2022 in Tehran (Iran). High-performance liquid chromatography was used to measure the serum concentration of INH and acetylisoniazid (AcINH). NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction and restriction fragment length polymorphism methods. Data were analyzed using SPSS software (version 22.0) with independent two-sample t test, Chi square test, or Fisher's exact test. P<0.05 was considered statistically significant.

Results: A total of 40 patients showed hepatotoxicity. The risk of anti-tuberculosis drug-induced hepatotoxicity was significantly higher in patients who are slow acetylator (SA) phenotype than in rapid or intermediate acetylator (P<0.001). NAT2*4/*4 genotypes were not found in patients with hepatotoxicity. The frequency of NAT2*5 and NAT2*6 haplotypes and serum INH concentration was significantly higher in patients with hepatotoxicity than in those without (P=0.003, P<0.001, and P<0.001, respectively). NAT2*4 haplotype was correlated with protection against hepatotoxicity. A combination of SA and CYP2E1 C1/C1 genotype was significantly associated with hepatotoxicity (P<0.001).

Conclusion: Hepatotoxicity in Iranian patients with tuberculosis was confirmed due to the presence of NAT2 SA polymorphism. Determining NAT2 and CYP2E1 genotypes and/or INH concentration can be a valuable tool to identify patients susceptible to hepatotoxicity.

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细胞色素P450 2E1和N-乙酰转移酶2基因型与血清异烟肼水平和抗结核药物诱导的肝毒性的相关性:一项横断面研究。
背景:抗结核药物引起的肝毒性可能是异烟肼代谢酶基因多态性的结果。本研究旨在确定N-乙酰转移酶2(NAT2)和细胞色素P4502E1(CYP2E1)基因的遗传多态性对血清异烟肼水平和药物诱导的肝毒性的影响。方法:2019年6月至2022年4月,在伊朗德黑兰对120名肺结核患者(有肝毒性和无肝毒性)进行了横断面研究。采用高效液相色谱法测定血清异烟肼和乙酰异烟肼浓度。采用聚合酶链式反应和限制性片段长度多态性方法测定NAT2和CYP2E1基因型。数据使用SPSS软件(22.0版)进行分析,采用独立双样本t检验、卡方检验或Fisher精确检验。结果:共有40例患者出现肝毒性。具有慢乙酰化(SA)表型的患者发生抗结核药物性肝毒性的风险显著高于快速或中等乙酰化(PNAT2*4/*4基因型在具有肝毒性的患者中未发现)。具有肝毒性患者的NAT2*5和NAT2*6单倍型的频率和血清INH浓度显著高于没有肝毒性患者(P=0.003,PNAT2*4单倍型与肝毒性保护相关。SA和CYP2E1 C1/C1基因型的组合与肝毒性显著相关(结论:伊朗肺结核患者的肝毒性是由于NAT2-SA多态性的存在而被证实的。测定NAT2和CYP2E1基因型和/或INH浓度可以成为识别易感肝毒性患者的有价值的工具。
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来源期刊
Iranian Journal of Medical Sciences
Iranian Journal of Medical Sciences MEDICINE, GENERAL & INTERNAL-
CiteScore
3.20
自引率
0.00%
发文量
84
审稿时长
12 weeks
期刊介绍: The Iranian Journal of Medical Sciences (IJMS) is an international quarterly biomedical publication, which is sponsored by Shiraz University of Medical Sciences. The IJMS intends to provide a scientific medium of com­muni­cation for researchers throughout the globe. The journal welcomes original clinical articles as well as clinically oriented basic science re­search experiences on prevalent diseases in the region and analysis of various regional problems.
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