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首页> 外文期刊>Pharmacogenetics and genomics >Molecular and genetic association of interleukin-6 in tacrine-induced hepatotoxicity.
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Molecular and genetic association of interleukin-6 in tacrine-induced hepatotoxicity.

机译：白细胞介素6在他克林诱导的肝毒性中的分子和遗传关联。

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BACKGROUND: Tacrine, an anticholinesterase used to treat Alzheimer's disease (AD), leads to an increase in serum alanine aminotransferase (ALT) levels. The factors determining individual susceptibility are largely unknown. The purpose of this study was to investigate genetic predisposition. METHODS: Rats were administered single dose tacrine (3-40 mg/kg). After 6 and 24 h, hepatic gene expression was determined using the affymetrix rat U34A microarray. On the basis of the gene expression data, the IL6 gene was identified as a potential candidate for tacrine transaminitis susceptibility. Sixty-nine patients with AD on tacrine with or without transaminitis were genotyped for 17 IL6 polymorphisms. RESULTS: Serum aspartate aminotransferase levels in rats increased after tacrine (40 mg/kg) administration. Forty-six and 29 genes showed significant upregulation at 6 and 24 h, respectively, after administration, including the IL-6-regulated acute phase response genes alpha2-macroglobulin, fibronectin and haptoglobin. Five of the 17 IL6 polymorphisms studied in AD patients showed an association (P<0.05) with transaminitis [ALT>2 x upper limit of normal (ULN)]. An association existed between maximum ALT and area under curve for ALT over 15 weeks and an intronic polymorphism (P<0.01) and a 3'-variable nucleotide tandem repeat (P<0.05). Multilocus haplotype analysis showed one haplotype (which included the -597A, -572G, -174G and variable nucleotide tandem repeat-D alleles) had a frequency of 0.1 in patients with ALT values >2 x ULN, whereas it was absent in patients with ALT less than 2 x ULN (P=0.0093, Pcorrected=0.049). CONCLUSION: The IL6 genotype may act as a predisposing factor for tacrine transaminitis. This, however, requires further confirmatory functional studies. The role of acute dosing rodent models in identifying candidate genes associated with drug-induced liver injury in man deserves further study.
机译：背景：他克林，一种用于治疗阿尔茨海默氏病（AD）的抗胆碱酯酶，导致血清丙氨酸氨基转移酶（ALT）水平升高。决定个体敏感性的因素在很大程度上是未知的。这项研究的目的是调查遗传易感性。方法：给大鼠服用单剂量他克林（3-40 mg / kg）。 6和24小时后，使用affymetrix大鼠U34A微阵列测定肝基因表达。根据基因表达数据，IL6基因被确定为他克林转氨酶易感性的潜在候选者。对69例他克林有或无转氨性炎的AD患者进行基因分型，确定其有17种IL6多态性。结果：他克林（40 mg / kg）给药后，大鼠血清天冬氨酸转氨酶水平升高。给药后的46和29个基因分别在给药后6和24小时显着上调，包括IL-6调节的急性期反应基因α2-巨球蛋白，纤连蛋白和触珠蛋白。在AD患者中研究的17种IL6多态性中，有5种表现为与氨氨基甲炎相关[P <0.05] [ALT> 2 x正常上限（ULN）]。 15周内最大ALT与ALT曲线下面积与内含子多态性（P <0.01）和3'-可变核苷酸串联重复序列（P <0.05）之间存在关联。多基因座单倍型分析显示，ALT值> 2 x ULN的患者中一种单倍型（包括-597A，-572G，-174G和可变核苷酸串联重复-D等位基因）的频率为0.1，而ALT患者则不存在小于2 x ULN（P = 0.0093，Pcorrected = 0.049）。结论：IL6基因型可能是他克林转氨酶的诱因。但是，这需要进一步的验证性功能研究。急性给药啮齿动物模型在鉴定与人的药物性肝损伤相关的候选基因中的作用值得进一步研究。

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