摘要
目的研究药物代谢酶N-乙酰基转移酶2（NAT2）、锰超氧化物歧化酶（MnSOD）的基因多态性与抗结核药物肝损害的关系，阐明抗结核药物性肝损害（antituberculosis drug—induced liver injury，ATDILI）的分子机制。方法通过PCR-DS方法分析101例有抗结核药物性肝损害的结核病患者（肝损害组）及107例无ATDILT的结核病患者（对照组）的NAT2及MnSOD的基因多态性，并分析它们与ATDILT之间的关系。分析NAT2基因多态性及MnSOD基因多态性联合作用与ATDILT的关系。结果肝损害组患者中，39．6％（40／101）为NAT2慢乙酰化基因型；对照组中，12．2％（13／107）为NAT2慢乙酰化基因型。NAT2慢乙酰化基因型者发生抗结核药物性肝损害的风险系数（OR）为4．74（95％CI：2．42～9．28；Z2=20．62，P〈0．05）。肝损害组中，MnSOD基因47位C／C基因型占9．9％（10／101）；对照组MnSOD47位C／C基因型占1．9％（2／107），两组比较MnSOD基因47位C／C基因型发生药物性肝损害OR值为5．77（95％CI：1．23～27．02；Х^2=6．165，P〈O．05）。根据患者NAT2基因型及MnSOD基因型检测结果，患者可分为4组，A组为同时具有NAT2快中乙酰化基因型及MnSOD基因47位T／T或T／C基因型的患者，B组为同时具有NAT2快中乙酰化基因型及MnSOD基因47位C／C基因型的患者，C组为同时具有NAT2慢乙酰化基因型及MnSOD基因47位T／T或T／C基因型的患者，D组为同时具有NAT2慢乙酰化基因型及MnSOD基因47位C／C基因型的患者。A组患者发生ATDILT的占36．8％（53／144），B组患者发生ATDILT的占66．7％（6／9），C组患者发生ATDILT的占74．5％（38／511，D组患者发生ATDILT的占100％（4／4），后3者与第1者比较，发生药物性肝损害的几率分别为无统计学差异（Х^2=3．188，P〉0．05），有统计学差异（Х^2=21．512，P〈0．05），有统计学差异（Х^2=4．166，P〈0．05）。�
Objective To study the relationship between the ATDILT and gene polymorphism of drug metabolizing enzymes （DME）, including NAT2, MnSOD, and to illuminate the molecular mechanism of ATDILT. Methods The genes of NAT2 from 101 TB cases with ATDILT and 107 TB cases without ATDILT were amplified and sequenced. Their genotypes were determined and the genotype frequencies were compared between cases and controls using SPSS12.0 software. The relationship between gene polymorphisms and ATDILT was analyzed. The effect of NAT2 genotype combined with MnSOD genotype on ATDILT was analyzed. Results There were 40 patients with slow acetylator （39.6%） in cases with hepatotoxicity and 13 with slow acetylator （12.2%） in controls without hepatotoxicity. Patients with slow acetylator genotype （OR=4.74, 95% CI=2.42-9.28;Х^2=20.62, P〈0.05） had a significantly higher risk of antituberculosis drug-induced hepatotoxicity than those with rapid or intermediate acetylator genotypes. There were 10 patients with MnSOD 47C/C genotype （9.9%） in cases with hepatotoxicity and 2 with MnSOD 47C/C genotype （1.9%）in controls without hepatotoxicity. The MnSOD 47C/C genotype （OR= 5.77, Х^2=6.165, P〈0.05） had higher risk of ATDILT than 47MnSOD T/T or T/C genotype. According to the NAT2 and MnSOD genotype, the patients were divided into the following four groups, the group A is the patients with rapid or media acetylator genotype of NAT2 combined with MnSOD 47T/T or T/C genotype, the group B is the patients with rapid or media acetylator genotype of NAT2 combined with MnSOD 47C/C genotype, the group C is the patients with slow acetylator genotype of NAT2 combined with MnSOD 47T/T or T/C genotype, the group D is the patients with slow acetylator genotype of NAT2 combined with MnSOD 47C/C genotype. Of the 144 patients in the group A, 53 （36.8%） developed to ATDILT; of the 9 patients in the group B, 6（66.7%） developed to ATDILT; of the 51 patients in the group C, 38（74.5%） developed to ATDILT; of the 4 patients
出处
《中国抗生素杂志》
CAS
CSCD
北大核心
2016年第1期70-75,共6页
Chinese Journal of Antibiotics
基金
北京市科技计划研发攻关类科研基金资助项目(No.D08050700640802)
北京市科技计划课题首都临床特色应用研究项目(No.Z121107001012145)
关键词
抗结核药物
肝损害
药物代谢酶
基因多态性
Liver injury
Anti-tuberculosis drugs
Drug metabolizing emzyme
Gene polymorphism
