直接的肝毒性肝细胞损伤通常不是由于药物所致,而是毒性代谢物。微粒体P-450类药物代谢酶尤其可能产生肝损害。化学性质稳定的药物被活化后产生烷化、芳化或酰化物质,这些代谢物与肝细胞的基本物质肝分子共价结合,引起坏死。Ⅲ区的坏死最严重,此处药物代谢酶浓度最高,血窦中氧张力最低。扑热息痛是个很好的例子,肝毒性与其亲电子的代谢物直接相关。治疗量的扑热息痛是无毒性的,但超剂量可致命。起初,毒性代谢物与肝的谷胱甘肽结合,当谷肽甘肽耗尽时,扑热息痛的代谢物主要芳化成亲核性大分子物质,从而导致肝坏死。在代谢物结合于组织之前,早期应用乙酰半胱氨酸治疗是有益的。醇的摄入可增加扑热息痛的肝毒性,致使剂量小 Direct liver toxicity Liver cell damage is not usually due to drugs, but toxic metabolites. In particular, microsomal P-450 drug metabolizing enzymes may cause liver damage. Chemically stable drugs are activated to produce alkylated, aroded or acylated substances that covalently bind to the liver cell’s essential substance, hepatic molecules, causing necrosis. The necrosis of area Ⅲ is the most serious, where the concentration of drug metabolizing enzyme is the highest and the oxygen tension in the sinus is the lowest. Paracetamol is a good example of hepatotoxicity directly related to its electrophilic metabolites. The amount of acetaminophen is non-toxic, but overdose can be fatal. Initially, the toxic metabolites bind to the hepatic glutathione. When glutathione is depleted, paracetamol metabolites are predominantly aromatic to nucleophilic macromolecules, leading to hepatic necrosis. Early administration of acetylcysteine ​​is beneficial before the metabolites bind to the tissue. Alcohol intake can increase the hepatotoxicity of paracetamol, resulting in a small dose