Kim Seung Hyun, Naisbitt Dean J
Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea.
MRC Centre for Drug Safety Science, Department of Clinical and Molecular Pharmacology, Sherrington Building, Ashton Street, The University of Liverpool, Liverpool, L69 3 GE, England.
Allergy Asthma Immunol Res. 2016 Jan;8(1):3-11. doi: 10.4168/aair.2016.8.1.3. Epub 2015 Jul 3.
Drug-induced liver injury (DILI) is a major concern for public health, as well as for drug development in the pharmaceutical industry, since it can cause liver failure and lead to drug withdrawal from the market and black box warnings. Thus, it is important to identify biomarkers for early prediction to increase our understanding of mechanisms underlying DILI that will ultimately aid in the exploration of novel therapeutic strategies to prevent or manage DILI. DILI can be subdivided into 'intrinsic' and 'idiosyncratic' categories, although the validity of this classification remains controversial. Idiosyncratic DILI occurs in a minority of susceptible individuals with a prolonged latency, while intrinsic DILI results from drug-induced direct hepatotoxicity over the course of a few days. The rare occurrence of idiosyncratic DILI requires multicenter collaborative investigations and phenotype standardization. Recent progress in research on idiosyncratic DILI is based on key developments in 3 areas: (1) newly developed high-throughput genotyping across the whole genome allowing for the identification of genetic susceptibility markers, (2) new mechanistic concepts on the pathogenesis of DILI revealing a key role of drug-responsive T lymphocytes in the immunological response, and (3) broad multidisciplinary approaches using different platform "-omics" technologies that have identified novel biomarkers for the prediction of DILI. An association of a specific human leukocyte antigen (HLA) allele with DILI has been reported for several drugs. HLA-restricted T-cell immune responses have also been investigated using lymphocytes and T-cell clones isolated from patients. A microRNA, miR-122, has been discovered as a promising biomarker for the early prediction of DILI. In this review, we summarize recent advances in research on idiosyncratic DILI with an understanding of the key role of adaptive immune systems.
药物性肝损伤（DILI）是公共卫生以及制药行业药物研发中的一个主要关注点，因为它可导致肝衰竭，并致使药物退市以及被加上黑框警告。因此，识别用于早期预测的生物标志物，以增进我们对DILI潜在机制的理解，最终有助于探索预防或管理DILI的新型治疗策略，这一点很重要。DILI可细分为“内在性”和“特异质性”两类，尽管这种分类的有效性仍存在争议。特异质性DILI发生在少数易感个体中，潜伏期较长，而内在性DILI是由药物在数天内引起的直接肝毒性所致。特异质性DILI的罕见发生需要多中心协作研究和表型标准化。特异质性DILI研究的最新进展基于三个领域的关键发展：（1）新开发的全基因组高通量基因分型，可用于识别遗传易感性标志物；（2）关于DILI发病机制的新机制概念，揭示了药物反应性T淋巴细胞在免疫反应中的关键作用；（3）使用不同“组学”技术平台的广泛多学科方法，已识别出用于预测DILI的新型生物标志物。已有报道称几种药物的特定人类白细胞抗原（HLA）等位基因与DILI有关联。也已使用从患者分离的淋巴细胞和T细胞克隆对HLA限制的T细胞免疫反应进行了研究。一种 microRNA，即miR-122，已被发现是一种有前景的DILI早期预测生物标志物。在本综述中，我们总结了特异质性DILI研究的最新进展，并了解了适应性免疫系统的关键作用。
