Selective inhibition of complex I by N-methylisoquinolinium ion and N-methyl-1,2,3,4-tetrahydroisoquinoline in isolated mitochondria prepared from mouse brain.
1,2,3,4-Tetrahydroisoquinoline (TIQ), which is structurally similar to MPTP, has been found in human brain and has been reported to inhibit the mitochondrial respiration as does 1-methyl-4-phenylpyridinium ion (MPP+). However, the potency of inhibition by TIQ is less than that of MPP+. In this study, we report the effects of N-methyl-1,2,3,4-tetrahydroisoquinoline (N-Me-TIQ) and N-methylisoquinolinium ion (N-Me-IQ+) on the mitochondrial electron transport system using mitochondria prepared from mouse brains. Five mM N-Me-TIQ and 500 microM N-Me-IQ+ inhibited complex I activity to 54% and 63% of the control, respectively. The IC50 of N-Me-TIQ and N-Me-IQ+ were approximately 6.5 mM and 650 microM, respectively. Neither substance inhibited complex II, III and IV activities. Kinetic analyses of N-Me-IQ+ on complex I activity revealed uncompetitive inhibition against NADH and non-competitive inhibition against ubiquinone. These inhibitory characteristics were the same to those of MPP+ and the inhibitory potency of N-Me-IQ+ on complex I activity was stronger than that of MPP+.
Suzuki
K
K
Department of Neurology, Jichi Medical School, Tochigi, Japan.
Mizuno
Y
Y
Yamauchi
Y
Y
Nagatsu
T
T
Mitsuo
Y
Y
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D015259:Dopamine Agents / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D044005:Tetrahydroisoquinolines
D015259:Dopamine Agents; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C048977:1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine; C050386:1-methyl-1,2,3,4-tetrahydroisoquinoline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D016660:NAD(P)H Dehydrogenase (Quinone)