Activation of chlorpromazine by the myeloperoxidase system of the human neutrophil.
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).
van Zyl
J M
JM
Department of Pharmacology, Medical School, University of Stellenbosch, Tygerberg, South Africa.
Basson
K
K
Kriegler
A
A
van der Walt
B J
BJ
D002746:Chlorpromazine / Q000378:metabolism* / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000187:drug effects; D005609:Free Radicals; D006801:Humans; D008706:Methemoglobin / Q000096:biosynthesis; D009504:Neutrophils / Q000201:enzymology*; D009195:Peroxidase / Q000378:metabolism*; D013954:Thyroglobulin / Q000187:drug effects / Q000378:metabolism*
D005609:Free Radicals; D008706:Methemoglobin; D013954:Thyroglobulin; D009195:Peroxidase; D002746:Chlorpromazine