Toxicological Significance of Mechanism-Based Inactivation of Cytochrome P450 Enzymes by Drugs
Toxicological Significance of Mechanism-Based Inactivation of Cytochrome P450 Enzymes by Drugs
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DOI：
10.1080/10408440701215233
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发表时间：
2007-01
影响因子：
5.9
通讯作者：
Y. Masubuchi;T. Horie
中科院分区：
文献类型：
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作者：
Y. Masubuchi;T. Horie
细胞色素 P450 (P450) 酶将外源物质氧化成化学反应性代谢物或中间体以及稳定的代谢物。如果产物的反应性非常高，它会与酶本身的一个或多个催化位点结合并使酶失活。这种现象被称为基于机制的失活。许多临床上重要的药物都是基于机制的灭活剂，包括大环内酯类抗生素、钙通道阻滞剂和选择性血清素摄取抑制剂，但并不总是在结构和药理学上相关。药物治疗期间 P450 失活会导致严重的药物相互作用，因为结合的不可逆性使得酶抑制在消除致病药物后得以延长。治疗指数窄的药物（如特非那定和阿司咪唑）的代谢抑制会导致毒性。另一方面，P450 失活后的命运和毒理学后果仍有待阐明，但有人认为 P450 的修饰和降解与某些形式的组织毒性有关。卟啉药物，如灰黄霉素，会引起基于机制的血红素失活，导致形成亚铁螯合酶抑制性 N-烷基化原卟啉，并导致卟啉症。还提出 P450 衍生的游离血红素参与氟烷诱导的肝毒性，催化铁参与顺铂诱导的肾毒性。服用替尼酸和二肼苯达嗪后，在肝炎中发现了针对P450的自身抗体。替尼酸被CYP2C9激活并与CYP2C9共价结合，由此形成的新抗原激活免疫系统，导致形成针对CYP2C9的自身抗体，称为抗肝/肾微粒体自身抗体2型，而自身抗体在药物性肝炎中的病理作用在很大程度上仍然存在未知。
Cytochrome P450 (P450) enzymes oxidize xenobiotics into chemically reactive metabolites or intermediates as well as into stable metabolites. If the reactivity of the product is very high, it binds to a catalytic site or sites of the enzyme itself and inactivates it. This phenomenon is referred to as mechanism-based inactivation. Many clinically important drugs are mechanism-based inactivators that include macrolide antibiotics, calcium channel blockers, and selective serotonin uptake inhibitors, but are not always structurally and pharmacologically related. The inactivation of P450s during drug therapy results in serious drug interactions, since irreversibility of the binding allows enzyme inhibition to be prolonged after elimination of the causal drug. The inhibition of the metabolism of drugs with narrow therapeutic indexes, such as terfenadine and astemizole, leads to toxicities. On the other hand, the fate of P450s after the inactivation and the toxicological consequences remains to be elucidated, while it has been suggested that P450s modified and degraded are involved in some forms of tissue toxicity. Porphyrinogenic drugs, such as griseofulvin, cause mechanism-based heme inactivation, leading to formation of ferrochelatase-inhibitory N-alkylated protoporphyrins and resulting in porphyria. Involvement of P450-derived free heme in halothane-induced hepatotoxicity and catalytic iron in cisplatin-induced nephrotoxicity has also been suggested. Autoantibodies against P450s have been found in hepatitis following administration of tienilic acid and dihydralazine.Tienilic acid is activated by and covalently bound to CYP2C9, and the neoantigens thus formed activate immune systems, resulting in the formation of an autoantibodydirected against CYP2C9, named anti-liver/kidney microsomal autoantibody type 2, whereas the pathological role of the autoantibodies in drug-induced hepatitis remains largely unknown.