Srivastava A, Maggs J L, Antoine D J, Williams D P, Smith D A, Park B K
Department of Pharmacology and Therapeutics, Centre for Drug Safety Science, School of Biomedical Sciences, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, UK.
Handb Exp Pharmacol. 2010(196):165-94. doi: 10.1007/978-3-642-00663-0_7.
Drugs are generally converted to biologically inactive forms and eliminated from the body, principally by hepatic metabolism. However, certain drugs undergo biotransformation to metabolites that can interfere with cellular functions through their intrinsic chemical reactivity towards glutathione, leading to thiol depletion, and functionally critical macromolecules, resulting in reversible modification, irreversible adduct formation, and irreversible loss of activity. There is now a great deal of evidence which shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, such as acetaminophen, tamoxifen, isoniazid, and amodiaquine. The main theme of this article is to review the evidence for chemically reactive metabolites being initiating factors for the multiple downstream biological events culminating in toxicity. The major objectives are to understand those idiosyncratic hepatotoxicities thought to be caused by chemically reactive metabolites and to define the role of toxic metabolites.
药物通常会转化为无生物活性的形式，并主要通过肝脏代谢从体内消除。然而，某些药物会进行生物转化生成代谢产物，这些代谢产物可通过其对谷胱甘肽的固有化学反应性干扰细胞功能，导致硫醇耗竭，并与功能关键的大分子发生反应，从而导致可逆性修饰、不可逆加合物形成以及不可逆的活性丧失。现在有大量证据表明，已知会导致肝毒性的药物，如对乙酰氨基酚、他莫昔芬、异烟肼和阿莫地喹，会形成反应性代谢产物。本文的主要主题是回顾关于化学反应性代谢产物作为导致毒性的多个下游生物事件起始因素的证据。主要目标是了解那些被认为由化学反应性代谢产物引起的特异质性肝毒性，并确定有毒代谢产物的作用。
