对乙酰氨基酚致药物性肝损伤的机制研究进展

Research advances in the mechanism of drug-induced liver injury due to paracetamol

药物性肝病又称药物性肝损伤,是我国非感染性肝病的第二大病种,美国肝衰竭/肝移植的首要原因。药物性肝损伤主要分为固有型肝损伤和非特异质型肝损伤。固有型药物性肝损伤在临床前安全研究中是无法被预测到的,而大多数药物引起的非特异质型肝毒性在临床前研究中就会被发现从而不会被应用到临床,但其中一个例外就是对乙酰氨基酚(扑热息痛,APAP),这种药物在治疗剂量之内是安全的,但是过量服用则会导致严重的肝损伤甚至急性肝衰竭。在欧美等发达国家,APAP过量服用是导致急性肝衰竭的主要原因。因此进一步阐明APAP引起肝损伤的细胞和分子机制,尤其是肝细胞死亡的机制,有助于尽早识别发生急性肝衰竭和不良预后的危险因素,从而有针对性的开发阻断肝损伤进程的治疗靶点与方案。

Drug-induced liver disease,also known as drug-induced liver injury( DILI),is the second largest cause of non-infectious liver disease in China and the leading cause of liver failure or liver transplantation in the United States.DILI is classified into idiosyncratic and dose-dependent DILI.Idiosyncratic DILI is currently not predictable in preclinical safety studies,while dose-dependent hepatotoxicity due to most drugs can be identified in preclinical safety studies,and thus these drugs are not used in clinical practice.One notable exception is paracetamol( APAP),which is safe within therapeutic dose,but an overdose of this drug may cause severe liver injury and even acute liver failure.APAP overdose is the major cause of acute liver failure in developed countries in Europe and America.Therefore,further clarification of cellular and molecular mechanisms of DILI due to APAP,especially the mechanism of hepatocyte death,may help with the early identification of risk factors for acute liver failure and poor prognosis and the development of treatment targets and regimens to block the progression of liver injury.