摘要
生物转化是化学诱导毒性的一个关键因素。虽然生物有一种本质的倾向:通过有或没有结构修饰以及化学试剂的排泄(排毒)来减少化学接触带来的伤害,但并非总是如此,毒性还是可能会形成。从解剖、生理、生化的角度,肝脏是生物转化的中心,它与胃和小肠相邻,接收到超过25%的心输出量。一般来说,它包含数量和种类最多的药物代谢酶。这就是为什么许多口服药物会引起肝毒性作用。然而,无肝脏组织的生物也可在体内产生毒性。虽然几个实例提出了肝脏中具有生物活性代谢物运输到靶组织的是毒性产生的原因,如野百合碱导致的肺毒性,四乙铅、正己烷导致的神经系统毒性和2-甲氧基乙醇导致的睾丸毒性等,但是绝大多数的数据显示肝外毒性产生的原因是存在于靶组织本身。肝外生物活化和药物毒性的影响也可以在由于不可承受毒性导致药物抗性时看到;不利的心血管效应是1993年到2006年之间药物停用的最主要原因。另一方面,母体药物和/或稳定代谢物(s)也可能导致不利影响,如抑制转运蛋白、阻塞胆汁分泌和细胞器的积累,如线粒体,这将导致肝脏和在其他器官中的脂肪变性。然而,本文试图总结只有肝外生物活化药物/化学制品及其在细胞和组织水平的影响。具体来说,它侧重于两个最灌注器官,肺部和心脏组织,以及甲状腺、血液、大脑、皮肤。本文综述了仍在使用的有严重问题的毒性药物 (粒细胞缺乏症和心血管毒性)——氯氮平,以及其他器官中特别强调的多种药物的肝外毒性。
关键词: 氯氮平,药物代谢,特殊的药物不良反应,线粒体,活性代谢物,靶器官
Current Medicinal Chemistry
Title:Extrahepatic Targets and Cellular Reactivity of Drug Metabolites
Volume: 22 Issue: 4
Author(s): Hilmi Orhan
Affiliation:
关键词: 氯氮平,药物代谢,特殊的药物不良反应,线粒体,活性代谢物,靶器官
摘要: Biotransformation is one of the key elements of chemically induced toxicity. Although organisms have an intrinsic tendency to diminish the harm posed by chemical exposure with or without structural modification and excretion of the agents (detoxification), this is not always the case; toxification may also occur. The liver has evolved to be the center of biotransformation from the anatomical, physiological and biochemical points of view; it is located alongside the stomach and intestine, it receives more than 25% of the cardiac output and it contains, in general, the richest quantity but also variety of drug metabolizing enzymes. That is why many orally taken drug-induced toxic effects are seen in the liver. Nevertheless, non-hepatic tissues in the organism are also subjected to toxic insult. Although several instances have suggested transport of liver-bioactivated reactive metabolites to the target tissue is responsible, such as monocrotaline-associated lung toxicity, tetraethyl lead- and n-hexane-associated nervous system toxicity and 2-methoxyethanol-associated testis toxicity, etc. [1], the vast majority of data show local bioactivation in the target tissue is responsible for the extrahepatic toxic outcome. The impact of extrahepatic bioactivation and toxicity of drugs can also be seen in cases of drug attrition due to unacceptable toxicity; adverse cardiovascular effects were the foremost reason for drug withdrawals between 1993 and 2006 [2]. On the other hand, the parent drug and/or its stable metabolite( s) may also cause adverse effects such as inhibition of transporters, occlusion of bile secretion (cholestasis) and accumulation in organelles such as mitochondria, causing steatosis in liver and possibly in other organs. However, this review attempts to summarize only extrahepatic bioactivation of drugs/chemicals and their effects at the cellular and tissue level. Specifically, it focuses on the two most perfused organs, lung and heart tissue, as well as thyroid, blood, brain, and skin. Clozapine, a still-in-use drug with severe off-target toxicities (agranulocytosis and cardiovascular toxicity), is investigated in depth and various drugs are reviewed with a special emphasize on the other mentioned organs.
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Cite this article as:
Hilmi Orhan , Extrahepatic Targets and Cellular Reactivity of Drug Metabolites, Current Medicinal Chemistry 2015; 22 (4) . https://dx.doi.org/10.2174/0929867321666140826113716
DOI https://dx.doi.org/10.2174/0929867321666140826113716 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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