Mitochondrial Superoxide Dismutase and Glutathione Peroxidase in Idiosyncratic Drug-Induced Liver Injury
Mitochondrial Superoxide Dismutase and Glutathione Peroxidase in Idiosyncratic Drug-Induced Liver Injury
复制标题
DOI：
10.1002/hep.23668
复制
发表时间：
2010-07-01
期刊：
影响因子：
13.5
通讯作者：
Agundez, Jose A. G.
中科院分区：
文献类型：
--
作者：
Lucena, M. Isabel;Garcia-Martin, Elena;Agundez, Jose A. G.
药物性肝损伤(DILI)的易感性有潜在的遗传基础。我们评估了发生DILI的风险与常见的锰超氧化物歧化酶(SOD2Val16Ala)和谷胱甘肽过氧化物酶(GPX1 Pro200Leu)基因变异之间的可能联系，这两个基因参与了线粒体氧化应激管理。分析了185名DILI患者和270名性别和年龄匹配的对照组的基因组DNA，这些患者的基因组DNA由国际医学科学理事会量表评估。分别采用聚合酶链式反应限制性片段长度多态性和TaqMan探针定量聚合酶链式反应进行SOD2和GPX1基因分型。在SOD2和GPX1的双侧关联中，用观察到的优势比(OR)来检测变异等位基因效应的统计能力分别为98.2%和99.7%。SOD2Ala/Ala基因型与胆汁淤积/混合性损伤相关(OR=2.3；95%可信区间[CI]=1.4~3.8；校正后P[Pc]=0.0058)，而GPX1Leu/Leu基因型与胆汁淤积损伤相关(OR=5.1；95%CI=1.6~16.0；Pc=0.0112)。在DILI患者中，SOD2Ala和GPX1Leu两个或两个以上组合风险等位基因的存在频率更高(OR=2.1；95%CI=1.4~3.0；Pc=0.0006)。线粒体危险药物所致胆汁淤积/混合性损伤患者更易发生SOD2Ala/Ala基因型(OR=3.6；95%CI=1.4~9.3；Pc=0.02)。在药物(OR=3.0；95%CI=1.7~5.5；Pc=0.0008)和S氧化物、二氮嗪、硝基阴离子或亚胺离子(OR=16.0；95%CI=1.8~146.1；Pc=0.009)所致的胆汁淤积/混合性DILI中，该基因频率也较高。结论：SOD2Ala等位基因和GPX1Leu等位基因纯合的患者发生胆汁淤积性DILI的风险较高。Sod2Ala纯合子可能更容易患上DILI的药物，这些药物对线粒体有害或产生活性中间体。(《肝病》2010；52：303-312)
Drug-induced liver injury (DILI) susceptibility has a potential genetic basis. We have evaluated possible associations between the risk of developing DILI and common genetic variants of the manganese superoxide dismutase (SOD2 Val16Ala) and glutathione peroxidase (GPX1 Pro200Leu) genes, which are involved in mitochondrial oxidative stress management. Genomic DNA from 185 DILI patients assessed by the Council for International Organizations of Medical Science scale and 270 sex- and age-matched controls were analyzed. The SOD2 and GPX1 genotyping was performed using polymerase chain reaction restriction fragment length polymorphism and TaqMan probed quantitative polymerase chain reaction, respectively. The statistical power to detect the effect of variant alleles with the observed odds ratio (OR) was 98.2% and 99.7% for bilateral association of SOD2 and GPX1, respectively. The SOD2 Ala/Ala genotype was associated with cholestatic/mixed damage (OR = 2.3; 95% confidence interval [CI] = 1.4-3.8; corrected P [Pc] = 0.0058), whereas the GPX1 Leu/Leu genotype was associated with cholestatic injury (OR = 5.1; 95%CI = 1.6-16.0; Pc = 0.0112). The presence of two or more combined risk alleles (SOD2 Ala and GPX1 Leu) was more frequent in DILI patients (OR = 2.1; 95%CI = 1.4-3.0; Pc = 0.0006). Patients with cholestatic/mixed injury induced by mitochondria hazardous drugs were more prone to have the SOD2 Ala/Ala genotype (OR = 3.6; 95%CI = 1.4-9.3; Pc = 0.02). This genotype was also more frequent in cholestatic/mixed DILI induced by pharmaceuticals producing quinone-like or epoxide metabolites (OR = 3.0; 95%CI = 1.7-5.5; Pc = 0.0008) and S-oxides, diazines, nitroanion radicals, or iminium ions (OR = 16.0; 95%CI = 1.8-146.1; Pc = 0.009). Conclusion: Patients homozygous for the SOD2 Ala allele and the GPX1 Leu allele are at higher risk of developing cholestatic DILI. SOD2 Ala homozygotes may be more prone to suffer DILI from drugs that are mitochondria hazardous or produce reactive intermediates. (HEPATOLOGY 2010;52:303-312)