Trimethoprim: Novel Reactive Intermediates and Bioactivation Pathways by Cytochrome P450s
Trimethoprim: Novel Reactive Intermediates and Bioactivation Pathways by Cytochrome P450s
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DOI：
10.1021/tx8002593
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发表时间：
2008-11-01
影响因子：
4.1
通讯作者：
Commandeur, Jan N. M.
中科院分区：
文献类型：
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作者：
Damsten, Micaela C.;de Vlieger, Jon S. B.;Commandeur, Jan N. M.
甲氧苄啶（TMP）是一种广泛使用的抗菌药物，通常被认为是一种安全的药物。然而，TMP与人类罕见的药物不良反应（ADR）有关。已提出活性亚氨基醌甲基化物中间体的生物活化是药物毒性的可能原因。然而，很少有人知道细胞色素P450（P450）参与这种生物活化和一般的TMP代谢。在这项研究中，我们研究了TMP的代谢和生物激活的人肝微粒体（HLM）和大鼠肝微粒体，重组人细胞色素P450，和细菌P450 BM 3突变体M11（his）。除非GSH依赖性代谢物外，在HLM孵育中还鉴别出5种GSH加合物。除了两种主要的GSH加合物可能来源于先前描述的亚氨基醌甲基化物中间体之外，还鉴定了三种次要的GSH加合物，这表明HLM形成了其他类型的反应性中间体，例如邻醌和对苯醌甲基化物中间体。主要的GSH加合物由P450 1A2和P450 3A4产生，而次要的GSH加合物主要由P450 1A2、P450 3A4和P450 2D6形成。虽然是初步的，但这些结果可能暗示P450酶的遗传多态性可能在人类TMP相关ADR的发生中发挥作用。
Trimethoprim (TMP) is a widely used antibacterial agent that is usually considered as a safe drug. TMP has, however, been implicated in rare adverse drug reactions (ADRs) in humans. Bioactivation to a reactive iminoquinone methide intermediate has been proposed as a possible cause for the toxicity of the drug. However, little is known about the cytochrome P450s (P450s) involved in this bioactivation and in the metabolism of TMP in general. In this study, we have investigated the metabolism and bioactivation of TMP by human liver microsomes (HLM) and rat liver microsomes, by recombinant human cytochrome P450s, and by the bacterial P450 BM3 mutant M11(his). In addition to non GSH-dependent metabolites, five GSH adducts were identified in the HLM incubations. Next to two major GSH adducts probably originating from the iminoquinone methide intermediate described previously, three minor GSH adducts were also identified, indicating that other types of reactive intermediates are formed by HLM, such as ortho-quinones and para-quinone methide intermediates. The major GSH adducts were produced by P450 1A2 and P450 3A4 while the minor GSH adducts were mainly formed by P450 1A2, P450 3A4, and P450 2D6. Although preliminary, these results might implicate that genetic polymorphisms in P450 enzymes could play a role in the onset of TMP-related ADRs in humans.