Modulation of the iodination reaction in normal human neutrophils and in whole blood by penicillamine, congeners and intracellular enzyme catalase and superoxide dismutase.
We have demonstrated that penicillamine (PSH) has the capacity to effect phagocytic cells by its interaction with the myeloperoxidase-halide system (MPOHS). We have undertaken studies at the cellular level, measuring the activity of the MPOHS through quantitation of I125 uptake (free and bound), known as the iodination reaction (i.e., in isolated polymorphonuclear leukocytes (PMN) and in whole blood). In contrast to other studies investigating the effects of PSH on isolated myeloperoxidase (MPO), we have shown that PSH scavenges the H2O2 produced by phagocytic cells, thereby reducing the availability of H2O2 for conversion to HOI125 by myeloperoxidase. This was observed as a reduction in the level of iodination. This finding is supported by our having obtained similar results in PMN and whole blood with catalase (C), glutathione (GSH) and N-acetylcysteine (NAC) but not with penicillamine disulphide (PSSP) or superoxide dismutase. Cu2+ (8 microM) when incubated with PSH reduced the level of inhibition of the iodination reaction by the oxidation of PSH to PSSP, illustrating the importance of the free sulphydryl group for this action. Incubation of PMN or whole blood for 0 to 2 hours with PSH, with a subsequent washing of PMN prior to stimulation, showed that PSH (free) requires to be present during stimulation of phagocytic cells to have this effect on the iodination reaction. Superoxide dismutase (SOD) produced increases in the iodination reaction in stimulated PMN by increasing the availability of H2O2. In conclusion, PSH inhibits the myeloperoxidase-halide system at a cellular level by scavenging H2O2 rather than by oxidation of the myeloperoxidase enzyme. This was observed at clinically relevant concentrations of PSH.
Mahlis
E
E
Department of Medicine, University of Melbourne, Heidelberg Victoria, Australia.
Christophidis
N
N
D002374:Catalase / Q000378:metabolism*; D003300:Copper / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007455:Iodine / Q000378:metabolism*; D007457:Iodine Radioisotopes; D009504:Neutrophils / Q000201:enzymology*; D010084:Oxidation-Reduction; D010396:Penicillamine / Q000378:metabolism / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*
D007457:Iodine Radioisotopes; D003300:Copper; D007455:Iodine; D006861:Hydrogen Peroxide; D002374:Catalase; D009195:Peroxidase; D013482:Superoxide Dismutase; D005978:Glutathione; D010396:Penicillamine