Ben Mahmoud L, Ghozzi H, Kamoun A, Hakim A, Hachicha H, Hammami S, Sahnoun Z, Zalila N, Makni H, Zeghal K
Department of Pharmacology, Faculty of medicine of Sfax, 3029 Sfax, Tunisia.
Pathol Biol (Paris). 2012 Oct;60(5):324-30. doi: 10.1016/j.patbio.2011.07.001.
Antituberculosis drug-induced hepatitis attributed to isoniazide (INH) is one of the most prevalent drug-induced liver injuries. INH is metabolized by hepatic N-acetyltransferase 2 (NAT2) to form hepatotoxins.
To evaluate whether polymorphism of the NAT2 gene was associated with antituberculosis drug-induced hepatotoxicity in Tunisian patients.
A total of 66 patients with tuberculosis (TB) who received anti-TB treatment were followed prospectively. Their NAT2 genotype was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We identified three single nucleotide polymorphisms (SNPs); 481C to T (NAT25B), 590G to A (NAT26A) and 857G to A (NAT2*7B). Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis.
Fourteen patients (21.2%) were diagnosed with anti-TB drug-induced hepatitis. None of the rapid acetylators-type patients have expressed serum aminotransferase elevation. Among patients with hepatotoxicity, slow acetylators-type patients had a higher risk of hepatotoxicity than intermediate acetylators (21.4% vs. 78.6%, P=0.01). Statistical analysis revealed that the frequency of a variant diplotypes, NAT25B/5B and NAT26A/6A, were significantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity (P=0.01, odds ratio [OR]=7.6 and P=0.029, OR=15, respectively). By contrast, the frequency of the rapid acetylation NAT2*4 allele was significantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P=0.02, OR=0.18). Moreover, 590G/G genotype was associated with decreased hepatotoxicity (P=0.01); by contrast, homozygous point mutation at position 481 and 590 were associated with a higher risk of hepatotoxicity (P=0.01).
Our results suggest that the slow-acetylator status of NAT2 is risk factor for INH-induced hepatotoxicity. Moreover, diplotypes, NAT25B/5B, NAT26A/6A, 481T/T and 590A/A, are useful new biomarkers for predicting anti-TB drug-induced hepatotoxicity.
异烟肼（INH）所致抗结核药物性肝炎是最常见的药物性肝损伤之一。INH经肝脏N - 乙酰基转移酶2（NAT2）代谢形成肝毒素。
评估突尼斯患者中NAT2基因多态性与抗结核药物性肝毒性是否相关。
前瞻性随访66例接受抗结核治疗的结核病（TB）患者。采用聚合酶链反应 - 限制性片段长度多态性（PCR - RFLP）法测定其NAT2基因型。我们鉴定出3个单核苷酸多态性（SNP）；481C突变为T（NAT25B）、590G突变为A（NAT26A）和857G突变为A（NAT2*7B）。采用单因素分析和逻辑回归分析评估异烟肼所致肝炎的危险因素。
14例患者（21.2%）被诊断为抗结核药物性肝炎。快速乙酰化型患者均未出现血清转氨酶升高。在发生肝毒性的患者中，慢乙酰化型患者发生肝毒性的风险高于中间乙酰化型患者（21.4%比78.6%，P = 0.01）。统计分析显示，与未发生肝毒性的TB患者相比，发生肝毒性的TB患者中变异双倍体型NAT25B/5B和NAT26A/No6A的频率显著增加（分别为P = 0.01，比值比[OR]=7.6；P = 0.029，OR = 15）。相比之下，发生肝毒性的TB患者中快速乙酰化NAT2*4等位基因的频率显著低于未发生肝毒性的患者（P = 0.02，OR = 0.18）。此外，590G/G基因型与肝毒性降低相关（P = 0.01）；相比之下，481和590位点的纯合点突变与肝毒性风险较高相关（P = 0.01）。
我们的结果表明，NAT2的慢乙酰化状态是INH所致肝毒性的危险因素。此外，双倍体型NAT25B/5B、NAT26A/6A、481T/T和590A/A是预测抗结核药物性肝毒性的有用新生物标志物。
