Pachkoria Ketevan, Lucena M Isabel, Molokhia Mariam, Cueto Raquel, Carballo Alfonso Serrano, Carvajal Alfonso, Andrade Raúl J
Clinical Pharmacology Service, University Hospital Virgen de la Victoria, School of Medicine, Málaga, Spain.
Curr Drug Saf. 2007 May;2(2):97-112. doi: 10.2174/157488607780598287.
The diagnosis of drug-induced liver injury (DILI) is challenging and based on complex diagnostic criteria. DILI falls into two main categories i) intrinsic "dose-dependent" Type A reactions ii) "idiosyncratic" or Type B reactions (which are usually not predictable). Idiosyncratic reactions can be immunoallergic (hypersensitivity), or metabolic, although overlap between categories can occur. The aim of this review is to summarise the general view of underlying mechanisms in DILI and to highlight individual risk factors for developing hepatotoxicity. Polymorphisms of bioactivation/toxification pathways through CYP450 enzymes (Phase I), detoxification reactions (Phase II) and excretion/transport (Phase III) are explored together with immunological factors that might determine DILI. The importance of establishing a multidisciplinary and multi-centric network to promote the understanding and research in hepatotoxicity is underlined. Challenges such as genetic analyses for association studies and whole genome studies, pharmacogenetic testing and future approaches to study DILI are considered. Knowledge regarding these operational mechanisms could provide further insight for the prospective identification of susceptible patients at risk of developing drug-induced hepatotoxicity.
药物性肝损伤（DILI）的诊断具有挑战性，且基于复杂的诊断标准。DILI主要分为两类：i）内在的“剂量依赖性”A型反应；ii）“特异质性”或B型反应（通常不可预测）。特异质性反应可以是免疫过敏（超敏反应）或代谢性的，尽管两类反应之间可能存在重叠。本综述的目的是总结DILI潜在机制的一般观点，并强调发生肝毒性的个体危险因素。探讨了通过细胞色素P450酶（I相）进行生物活化/毒性化途径、解毒反应（II相）以及排泄/转运（III相）的多态性，以及可能决定DILI的免疫因素。强调了建立多学科、多中心网络以促进对肝毒性的理解和研究的重要性。考虑了诸如关联研究和全基因组研究的遗传分析、药物遗传学检测以及未来研究DILI的方法等挑战。关于这些作用机制的知识可为前瞻性识别有发生药物性肝毒性风险的易感患者提供进一步的见解。
