对乙酰氨基酚
代谢物
氧化应激
化学
细胞色素P450
线粒体通透性转换孔
解毒剂
谷胱甘肽
药理学
乙酰半胱氨酸
毒性
线粒体
生物化学
新陈代谢
酶
抗氧化剂
生物
程序性细胞死亡
细胞凋亡
有机化学
作者
Mitchell R. McGill,Jack Hinson
标识
DOI:10.1080/03602532.2020.1832112
摘要
Acetaminophen (APAP) was first synthesized in the 1800s, and came on the market approximately 65 years ago. Since then, it has become one of the most used drugs in the world. However, it is also a major cause of acute liver failure. Early investigations of the mechanisms of toxicity revealed that cytochrome P450 enzymes catalyze formation of a reactive metabolite in the liver that depletes glutathione and covalently binds to proteins. That work led to the introduction of N-acetylcysteine (NAC) as an antidote for APAP overdose. Subsequent studies identified the reactive metabolite N-acetyl-p-benzoquinone imine, specific P450 enzymes involved, the mechanism of P450-mediated oxidation, and major adducted proteins. Significant gaps remain in our understanding of the mechanisms downstream of metabolism, but several events appear critical. These events include development of an initial oxidative stress, reactive nitrogen formation, altered calcium flux, JNK activation and mitochondrial translocation, inhibition of mitochondrial respiration, the mitochondrial permeability transition, and nuclear DNA fragmentation. Additional research is necessary to complete our knowledge of the toxicity, such as the source of the initial oxidative stress, and to greatly improve our understanding of liver regeneration after APAP overdose. A better understanding of these mechanisms may lead to additional treatment options. Even though NAC is an excellent antidote, its effectiveness is limited to the first 16 hours following overdose.
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