[The effects of 1-methyl-4-phenylpyridine (MPP+) on O2- generation by neutrophils].

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces parkinsonisms in humans, monkeys, and some animals. MPTP is metabolized to 1-methyl-4-phenylpyridine (MPP+), which is a primary neurotoxin, by monoamine oxidase B. MPP+ destroys nigro-striatal dopaminergic neurons, but the mechanism of the neurotoxic effects of MPP+ is not known. In this study, the effects of MPP+ on O2- generation by neutrophils was examined. Neutrophils possess several functional and antigenic similarities to glial cells. Therefore, the O2- generating system of neutrophils might be useful in studying the mechanism of MPP+ neurotoxicity related to active oxygen species. 1) MPP+ did not affect myristic acid (MA), and elaidic acid stimulated O2- generation and H2O2 generation by the glucose-glucose oxidase system, suggesting that MPP+ did not react with O2- or H2O2 itself. 2) When fatty acid-activated neutrophils were treated with a neutral detergent, Renex 30, and then NADPH was added, the O2- generation by these permeabilized cells was inhibited by MPP+. 3) Kinetic study revealed that MPP+ was a noncompetitive inhibitor of the NADPH oxidase in plasma membranes isolated from MA-activated pig neutrophils. These results did not support the hypothesis that the action of MPP+ is related to active oxygen species. The results suggest that MPP+ does not penetrate through the plasma membrane, and interacts with the inner domain of NADPH oxidase in the neutrophil plasma membranes.