Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
Molecular Medicine Laboratory, Department of Pathology, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Iran J Med Sci. 2023 Sep;48(5):474-483. doi: 10.30476/ijms.2023.96145.2765.
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 () and cytochrome P450 2E1 () genes on serum isoniazid level and drug-induced hepatotoxicity.
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). and 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 test, Chi square test, or Fisher's exac test. P<0.05 was considered statistically significant.
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). *4/*4 genotypes were not found in patients with hepatotoxicity. The frequency of *5 and *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). *4 haplotype was correlated with protection against hepatotoxicity. A combination of SA and C1/C1 genotype was significantly associated with hepatotoxicity (P<0.001).
Hepatotoxicity in Iranian patients with tuberculosis was confirmed due to the presence of SA polymorphism. Determining and genotypes and/or INH concentration can be a valuable tool to identify patients susceptible to hepatotoxicity.
抗结核药物引起的肝毒性可能源于异烟肼（INH）代谢酶的基因遗传多态性。本研究旨在确定 N-乙酰转移酶 2（）和细胞色素 P450 2E1（）基因的遗传多态性对血清异烟肼水平和药物性肝毒性的影响。
本横断面研究于 2019 年 6 月至 2022 年 4 月在德黑兰（伊朗）对 120 例（有或无肝毒性）肺结核患者进行，采用高效液相色谱法测定血清异烟肼和乙酰异烟肼（AcINH）浓度。采用聚合酶链反应和限制性片段长度多态性方法检测和基因型。采用 SPSS 软件（版本 22.0）进行数据分析，采用独立样本 t 检验、卡方检验或 Fisher 确切概率法。P<0.05 为统计学显著。
共 40 例患者出现肝毒性。与快速或中间乙酰化者相比，慢乙酰化者（SA）表型发生抗结核药物性肝毒性的风险显著更高（P<0.001）。未在有肝毒性的患者中发现4/4 基因型。与无肝毒性者相比，有肝毒性者的5 和6 单倍型及血清 INH 浓度显著更高（P=0.003、P<0.001 和 P<0.001）。*4 单倍型与肝毒性保护相关。SA 与 C1/C1 基因型的组合与肝毒性显著相关（P<0.001）。
伊朗肺结核患者的肝毒性确认为 SA 多态性所致。确定和基因型和/或 INH 浓度可以成为识别易发生肝毒性患者的有价值工具。
