Ramappa Vidyasagar, Aithal Guruprasad P
NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK.
J Clin Exp Hepatol. 2013 Mar;3(1):37-49. doi: 10.1016/j.jceh.2012.12.001. Epub 2012 Dec 20.
Development of idiosyncratic hepatotoxicity is an intricate process involving both concurrent as well as sequential events determining the direction of the pathways, degree of liver injury and its outcome. Decades of clinical observation have identified a number of drug and host related factors that are associated with an increased risk of antituberculous drug-induced hepatotoxicity, although majority of the studies are retrospective with varied case definitions and sample sizes. Investigations on genetic susceptibility to hepatotoxicity have so far focused on formation and accumulation reactive metabolite as well as factors that contribute to cellular antioxidant defense mechanisms and the environment which can modulate the threshold for hepatocyte death secondary to oxidative stress. Recent advances in pharmacogenetics have promised the development of refined algorithms including drug, host and environmental risk factors that allow better tailoring of medications based on accurate estimates of risk-benefit ratio. Future investigations exploring the pathogenesis of hepatotoxicity should be performed using human tissue and samples whenever possible, so that the novel findings can be translated readily into clinical applications.
特异质性肝毒性的发生是一个复杂的过程，涉及同时发生以及相继发生的事件，这些事件决定了途径的方向、肝损伤的程度及其结果。数十年的临床观察已经确定了一些与药物和宿主相关的因素，这些因素与抗结核药物性肝毒性风险增加有关，尽管大多数研究都是回顾性的，病例定义和样本量各不相同。迄今为止，关于肝毒性遗传易感性的研究主要集中在反应性代谢产物的形成和积累，以及有助于细胞抗氧化防御机制的因素和能够调节氧化应激继发肝细胞死亡阈值的环境。药物遗传学的最新进展有望开发出更精细的算法，包括药物、宿主和环境风险因素，从而能够根据准确的风险效益比估计更好地调整用药。未来探索肝毒性发病机制的研究应尽可能使用人体组织和样本，以便新发现能够迅速转化为临床应用。
