N-acetyltransferase 2 (NAT2) gene polymorphism as a predisposing factor for phenytoin intoxication in tuberculous meningitis or tuberculoma patients having seizures - A pilot study
N-acetyltransferase 2 (NAT2) gene polymorphism as a predisposing factor for phenytoin intoxication in tuberculous meningitis or tuberculoma patients having seizures - A pilot study
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N-乙酰转移酶 2 (NAT2) 基因多态性作为结核性脑膜炎或结核瘤癫痫患者苯妥英中毒的诱发因素 - 一项初步研究
DOI：
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Sadhna Sharma
中科院分区：
文献类型：
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作者：
P. Adole;P. Kharbanda;Sadhna Sharma
背景和目标：结核性脑膜炎（TBM）或结核球患者同时服用苯妥英钠和异烟肼（INH）可导致苯妥英钠血药浓度升高，从而引起苯妥英钠中毒。N-乙酰基转移酶2（NAT 2）催化INH代谢中的两个乙酰化反应，NAT 2基因多态性导致缓慢和快速乙酰化。本研究的目的是评估N-乙酰转移酶2（NAT 2）基因的等位基因变异作为结核性脑脊髓炎（TBM）或结核瘤伴癫痫发作患者同时服用INH和苯妥英钠时苯妥英钠毒性的易感因素的作用。研究方法：60例患有结核性脑膜炎或结核瘤并伴有癫痫发作的患者同时服用INH和苯妥英至少7天。采用高效液相色谱法测定血浆苯妥英钠浓度。采用限制性片段长度多态性分析和等位基因特异性PCR方法研究NAT 2基因多态性。结果如下：将患者分为苯妥英钠中毒组和苯妥英钠水平正常组，并通过NAT 2基因分型将患者分为快速乙酰化组和缓慢乙酰化组。基因型分析显示，在所研究的7个NAT 2基因单核苷酸多态性（single nucleotide polymorphisms，SNP）中，发现6个突变与苯妥英钠中毒相关。苯妥英中毒组rs 1041983（C282 T）、rs 1799929（C481 T）、rs 1799931（G857 A）、rs 1799930（G590 A）、rs 1208（A803 G）和rs 1801280（T341 C）等位基因变异纯合突变比例高于苯妥英非中毒组。解释和结论：NAT 2基因481位点纯合突变等位基因可能是结核性脑脊髓炎或结核瘤患者癫痫发作时苯妥英钠中毒的易感因素。
Background & objectives: Simultaneous administration of phenytoin and isoniazid (INH) in tuberculous meningitis (TBM) or tuberculoma patients with seizures results in higher plasma phenytoin level and thus phenytoin intoxication. N-acetyltransferase 2 (NAT2) enzyme catalyses two acetylation reactions in INH metabolism and NAT2 gene polymorphism leads to slow and rapid acetylators. The present study was aimed to evaluate the effect of allelic variants of N-acetyltransferase 2 (NAT2) gene as a predisposing factor for phenytoin toxicity in patients with TBM or tuberculoma having seizures, and taking INH and phenytoin simultaneously. Methods: Sixty patients with TBM or tuberculoma with seizures and taking INH and phenytoin simultaneously for a minimum period of seven days were included in study. Plasma phenytoin was measured by high performance liquid chromatography. NAT2 gene polymorphism was studied using restriction fragment length polymorphism and allele specific PCR. Results: The patients were grouped into those having phenytoin intoxication and those with normal phenytoin level, and also classified as rapid or slow acetylators by NAT2 genotyping. Genotypic analysis showed that of the seven SNPs (single nucleotide polymorphisms) of NAT2 gene studied, six mutations were found to be associated with phenytoin intoxication. For rs1041983 (C282T), rs1799929 (C481T), rs1799931 (G857A), rs1799930 (G590A), rs1208 (A803G) and rs1801280 (T341C) allelic variants, the proportion of homozygous mutant was higher in phenytoin intoxicated group than in phenytoin non-intoxicated group. Interpretation & conclusions: Homozygous mutant allele of NAT2 gene at 481site may act as a predisposing factor for phenytoin intoxication among TBM or tuberculoma patients having seizures.
影响因子：
7.7
作者：
Roshandel D;Klein R;Klein BE;Wolffenbuttel BH;van der Klauw MM;van Vliet-Ostaptchouk JV;Atzmon G;Ben-Avraham D;Crandall JP;Barzilai N;Bull SB;Canty AJ;Hosseini SM;Hiraki LT;Maynard J;Sell DR;Monnier VM;Cleary PA;Braffett BH;DCCT/EDIC Research Group;Paterson AD
通讯作者：
Paterson AD