Biochemical mechanisms in drug-induced liver injury:Certainties and doubts

作     者：Ignazio Grattagliano Leonilde Bonfrate Catia V Diogo Helen H Wang David QH Wang Piero Portincasa 

作者机构：Clinica Medica "A.Murri"Dipartimento di Medicina Interna e Medicina PubblicaUniversity of Bari Medical School Department of ZoologyCenter for Neurosciences and Cell BiologyUniversity of Coimbra Department of MedicineLiver Center and Gastroenterology DivisionBeth Israel Deaconess Medical CenterHarvard Medical School and Harvard Digestive Diseases Center 

出 版 物：《World Journal of Gastroenterology》 (世界胃肠病学杂志（英文版）)

年 卷 期：2009年第15卷第39期

页      面：4865-4876页

核心收录：

学科分类：1002[医学-临床医学] 10[医学] 

主　　题：生化机制 肝损伤 药物性 免疫系统激活 肝细胞损伤 毒性机制 肝脏疾病 抗氧化剂 

摘      要：Drug-induced liver injury is a significant and still unresolved clinical problem.Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development.Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites.Aging,preexisting liver disease,enzyme induction or inhibition,genetic variances,local O2 supply and,above all,the intrinsic molecular properties of the drug may affect this process.Necrotic death follows antioxidant consumption and oxidation of intracellular proteins,which determine increased permeability of mitochondrial membranes,loss of potential,decreased ATP synthesis,inhibition of Ca2+-dependent ATPase,reduced capability to sequester Ca2+ within mitochondria,and membrane bleb formation.Conversely,activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis.Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage.Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis,in which different HLA genotypes might play a major role.This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage.Future perspectives including new frontiers for research are discussed.