Uetrecht J, Zahid N, Tehim A, Fu J M, Rakhit S
Faculty of Pharmacy and Medicine, University of Toronto, Canada.
Chem Biol Interact. 1997 May 2;104(2-3):117-29. doi: 10.1016/s0009-2797(97)00017-3.
Clozapine is associated with a high incidence of agranulocytosis. We had previously found that it is oxidized by granulocytes, or simply HOCl, to a reactive metabolite that irreversibly binds to the cells, and we proposed that this reactive metabolite is responsible for clozapine-induced agranulocytosis. The reactive metabolite appeared to be a nitrenium ion formed by chlorination of the nitrogen bridge between the two aromatic rings. If this is correct, analogs that contain this structural feature should also be oxidized to a reactive intermediate while those not possessing this feature would, at least, not form the same type of reactive intermediate and, therefore, may not induce agranulocytosis. We tested the first part of this hypothesis with three clozapine analogs that do contain a nitrogen bridge and three that do not. Consistent with the hypothesis, the three analogs that do contain the nitrogen bridge formed reactive intermediates that could be trapped with glutathione when oxidized by HOCl, myeloperoxidase or activated neutrophils. In contrast, we found no evidence of a reactive intermediate on oxidation of analogs that contained an oxygen or sulfur bridge rather than a nitrogen bridge. If such reactive metabolites are responsible for drug-induced agranulocytosis, it should be possible to use such a simple screening method to test drugs at an early stage in their development for the potential to induce agranulocytosis.
氯氮平与粒细胞缺乏症的高发生率相关。我们之前发现它会被粒细胞（或仅仅是次氯酸）氧化成一种活性代谢物，该代谢物会与细胞不可逆地结合，并且我们提出这种活性代谢物是氯氮平诱发粒细胞缺乏症的原因。这种活性代谢物似乎是由两个芳香环之间的氮桥氯化形成的氮鎓离子。如果这是正确的，那么含有这种结构特征的类似物也应该被氧化成一种活性中间体，而那些不具备这种特征的类似物，至少不会形成相同类型的活性中间体，因此可能不会诱发粒细胞缺乏症。我们用三种含有氮桥的氯氮平类似物和三种不含氮桥的类似物对这一假设的第一部分进行了测试。与该假设一致，三种含有氮桥的类似物在被次氯酸、髓过氧化物酶或活化的中性粒细胞氧化时会形成活性中间体，这些中间体可以被谷胱甘肽捕获。相比之下，我们没有发现含有氧桥或硫桥而非氮桥的类似物氧化时产生活性中间体的证据。如果这种活性代谢物是药物诱发粒细胞缺乏症的原因，那么应该可以使用这样一种简单的筛选方法在药物研发的早期阶段测试其诱发粒细胞缺乏症的可能性。
