The relation between respiratory inhibition and uptake of 1-methyl-isoquinoline (MIQ+) in mitochondria.
The effect of 1-methyl-isoquinoline (MIQ+) on the respiratory inhibition and the uptake of MIQ+ were measured using mouse liver mitochondria. MIQ+ inhibited the electron transport of complex I but did not inhibit the respiration of mitochondria with succinate as a substrate. MIQ+ was taken up by mitochondria in an energy dependent process. Tetraphenylboron enhanced the MIQ+ uptake by mitochondria and its inhibitory effect on respiration. The respiratory inhibition of mitochondria by MIQ+ resulted in release of MIQ+ from mitochondria in medium containing glutamate and malate. These characteristics of MIQ+, for uptake into mitochondria and respiratory inhibition, were similar to those of 1-methyl-4-phenylpyridine (MPP+). The IC50 of MIQ+ for respiratory inhibition was higher than that of MPP+, and the amount of MIQ+ uptake by mitochondria was smaller that of MPP+. The lower ability of MIQ+ for respiratory inhibition as compared to that of MPP+ must result from the lower lipophilic ability of MIQ+ than that of MPP+. These results show that, unlike MPP+, MIQ+ cannot act as a rapid neurotoxin. But, it does not eliminate the possibility that MIQ+ acts as a neurotoxin in the long-term, since MIQ+ was taken up in mitochondria and inhibited the respiration.
Aiuchi
T
T
Laboratory of Biological Chemistry, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Matsunaga
M
M
Syo
M
M
Nakaya
K
K
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D002138:Calibration; D019069:Cell Respiration / Q000187:drug effects*; D015259:Dopamine Agents / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008839:Microelectrodes; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D013775:Tetraphenylborate / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
D015259:Dopamine Agents; D007202:Indicators and Reagents; D007546:Isoquinolines; D014475:Uncoupling Agents; D013775:Tetraphenylborate; D015655:1-Methyl-4-phenylpyridinium; C103464:1-methylisoquinoline