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.