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Effects of 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine and 1‐Methyl‐4‐Phenylpyridinium Ion on Activities of the Enzymes in the Electron Transport System in Mouse Brain

Abstract: The effects of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahy‐dropyridine (MPTP) and 1‐methyl‐4‐phenylpyridinium ion (MPP+) on activities of enzyme complexes in the electron transport system were studied using isolated mitochondrial preparations from C57BL/6J mouse brains. Both MPTP and MPP+ dose‐dependently inhibited activity of NADH‐ubiquinone oxidoreductase (EC 1.6.5.3). The inhibition was reversible. Preincubation of freeze‐thawed mitochondria with MPTP or MPP+ had no effect on the inhibition; however, when nonfrozen mitochondria were used, NADH‐ubiquinone oxidoreductase activity was reduced to 46% of that in the nonincubated sample after a 5‐min preincubation with MPTP and to 77% of that in the nonincubated sample after a 5‐min preincubation with MPP+. Kinetic analyses revealed that inhibition of MPTP was non‐competitive and that of MPP+ uncompetitive with respect to NADH. On the other hand, inhibition of MPTP was uncompetitive and that of MPP+ noncompetitive with respect to ubiquinone. Succinate – ubiquinone oxidoreductase (complex II), dihydroubiquinone‐cytochrome c oxidoreductase (complex III), and ferrocytochrome c‐oxygen oxidoreductase (EC 1.9.3.1) activities were either slightly inhibited or not inhibited by MPTP or MPP+. The significance of these findings is discussed in relation to the mechanism of MPTP‐induced neuronal degeneration.