人中性粒细胞髓过氧化物酶系统对氯丙嗪的激活作用。

Activation of chlorpromazine by the myeloperoxidase system of the human neutrophil.

作者信息

van Zyl J M, Basson K, Kriegler A, van der Walt B J

机构信息

Department of Pharmacology, Medical School, University of Stellenbosch, Tygerberg, South Africa.

出版信息

Biochem Pharmacol. 1990 Sep 1;40(5):947-54. doi: 10.1016/0006-2952(90)90478-4.

DOI:10.1016/0006-2952(90)90478-4

PMID:2167682

Abstract

The univalent oxidation of chlorpromazine (CPZ) by the myeloperoxidase (MPO-H2O2) system led to the formation of a cation free radical (CPZ+) which was observed optically at 527 nm. CPZ protected MPO against loss of catalytic activity when co-oxidized in a MPO-Cl(-)-H2O2 system. Due to the stability of CPZ+ either further oxidation, or reduction back to the mother compound, become important mechanisms for disappearance of the free radical. Thus, the rate of formation and decay of CPZ+ were higher in the presence of Cl- than in its absence, since the radical can also be oxidized further by hypochlorous acid (HOCl), which is formed in the MPO-Cl(-)-H2O2 system. Decay of CPZ+ can also be due to electron acceptance from ascorbic acid or oxygenated haemoglobin (HbO2), resulting in regeneration of CPZ. When CPZ+ was generated in the MPO-H2O2 system, addition of HbO2 resulted in a sudden decrease in CPZ+ absorbance at 527 nm and a concomitant formation of metHb. When HbO2 was not added, the decay of CPZ+ was much slower. CPZ (in the absence of the MPO system) also stimulated the oxidation of HbO2 in the presence of 20 microM H2O2, but this reaction was considerably slower than when CPZ+ (generated by the MPO system) was allowed to react directly with HbO2. These results suggest that HbO2 was oxidized by CPZ+. To study the effect of CPZ intermediates, thyroglobulin (TG) was used as a model polypeptide. Chlorinated oxidants formed in the MPO system (in the absence of CPZ) induced TG peptide bond splitting. In contrast, CPZ metabolites generated by the MPO system (in the absence of Cl-) induced polymerization of TG, as revealed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE).

摘要

氯丙嗪（CPZ）在髓过氧化物酶（MPO-H₂O₂）系统中的单价氧化导致形成阳离子自由基（CPZ⁺），该自由基在527 nm处可通过光学方法观察到。当在MPO-Cl⁻-H₂O₂系统中共同氧化时，CPZ保护MPO免受催化活性的损失。由于CPZ⁺的稳定性，进一步氧化或还原回母体化合物成为自由基消失的重要机制。因此，在存在Cl⁻的情况下，CPZ⁺的形成和衰减速率高于不存在Cl⁻时，因为该自由基也可被MPO-Cl⁻-H₂O₂系统中形成的次氯酸（HOCl）进一步氧化。CPZ⁺的衰减也可能是由于抗坏血酸或氧化血红蛋白（HbO₂）接受电子，导致CPZ再生。当在MPO-H₂O₂系统中生成CPZ⁺时，加入HbO₂会导致527 nm处CPZ⁺吸光度突然下降，并伴随高铁血红蛋白（metHb）的形成。当不加入HbO₂时，CPZ⁺的衰减要慢得多。在20 μM H₂O₂存在的情况下，CPZ（在不存在MPO系统时）也会刺激HbO₂的氧化，但该反应比MPO系统生成的CPZ⁺直接与HbO₂反应时要慢得多。这些结果表明HbO₂被CPZ⁺氧化。为了研究CPZ中间体的作用，使用甲状腺球蛋白（TG）作为模型多肽。在MPO系统中（不存在CPZ时）形成的氯化氧化剂诱导TG肽键断裂。相反，如十二烷基硫酸钠-聚丙烯酰胺凝胶电泳（SDS-PAGE）所示，MPO系统（不存在Cl⁻时）产生的CPZ代谢产物诱导TG聚合。