NAT2基因型、抗结核药物治疗对患者血浆浓度及肝功能异常的相关性研究

The Research on the Correlation among NAT2 Gene,the Plasma Concentration of Anti-Tuberculosis Drugs and the Liver Function Abnornal in Tuberculosis Patients

目的分析与探讨结核患者不同N-乙酰基转移酶2(NAT2)基因型分型和服用抗结核药物治疗后血浆浓度与肝功能异常的相关性,为临床根据NAT2基因分型指导抗结核药物合理用药提供依据。方法选取我院在2013年2月~2014年12月收治的肺结核患者50例为研究对象,回顾性分析患者的临床资料,并采用高效液相色谱法(HPLC)测定血浆中异烟肼(INH)的浓度,提取患者DNA,采用PCR-直接测序法(PCRDS)测定结核病患者NAT2基因型,记录肝功能检测结果,并进行相关性分析。结果患者接受氨基水杨酸异烟肼片(PAS-INH)治疗后,肝功能异常组和正常组的血浆药物浓度分别是(2.37±0.47)mg·L^(-1)、(1.78±0.52)mg·L^(-1),两组间差异具有统计学意义(P<0.05);20例NAT2RA(快速乙酰化)基因型,其中肝功能正常15例(75.0%),肝功能异常4例,1例出现ATDILI;26例IA(中等乙酰化)基因型,其中肝功能正常10例,16例肝功能异常,0例出现ATDILI。4例SA(慢速乙酰化)基因型,肝功能正常1例,肝功能异常1例,其中2例出现ATDILI。RA基因型肝功能异常率明显比SA基因型患者低(P=0.02,P<0.05),具有统计学意义。结论 NAT2基因型、抗结核药物浓度和ATDILI具有相关性,而且通过检测患者的NAT2基因型分型对其合理服用抗结核药物、预防抗结核药物导致的肝功能异常或者肝损伤等极具重要意义。检测血药浓度对结核药物造成肝功能异常或者肝损伤的预防意义仍有待考证。

OBJECTIVE To investigate the correlation between N-acetyltransferase2（ NAT2） genotype and concentrations of isoniazid（ INH） in the plasma of tuberculosis（ TB） patients after taking isoniazid aminosalicylate tablets（ PAS-INH）,so as to provide a basis for the guidance of rational use of PAS-INH by NAT2 genotyping. METHODS To analyze retrospectively the clinical data of 50 cases of TB patients in our hospital from Feb. 2013 to Dec. 2014. The concentration of INH in the plasma from 50 TB patients was determined by a highperformance liquid chromatography（ HPLC） 2 h after taking PAS-INH. The genomic DNAs of blood cells were extracted,and then NAT2 genotypes were analyzed by PCR-direct sequencing（ PCR-DS）. The relativity analysis of the main index sign of the liver function was performed. RESULTS After taking anti-TB drugs,The concentration of INH in the plasma of hepatic function abnormal group and normal group were（ 2. 37 ± 0. 47） mg·L^-1,（ 1. 78 ± 0. 52） mg·L^-1,respectively. Two sets of data between a statistically significant difference（ P〈0. 05）. Of the 50 TB cases,20 cases were rapid acetylation（ RA） genotype,15 cases were liver function normal,4 cases were antituberculosis druginduced liver injured（ ATDILI）,1 cases had ATDILI. 26 cases were intermediate acetylation（ IA genotype,10 cases were liver function normal,16 cases were liver function abnormal,0 cases had ATDILI. 4 cases were slow acetylation（ SA） genotype,SA-type have a significantly lower incidence of liver function abnormalities than RA-type cases（ P =0. 02,P〈0. 05）. CONCLUSION NAT2 genotype,plssma concentrations of anti-tuberculosis drugs and the liver function in TB patients have relativity. NAT2 genotyping may have important guiding significance for rational use of PAS-INH in the TB patients. The significance of testing concentrations of INH in the plasma needs further study.