L-Deprenyl as an inhibitor of menadione-induced permeability transition in liver mitochondria.
L-Deprenyl, an inhibitor of mitochondrial monoamine oxidase B (MAO B), inhibits the swelling of liver mitochondria induced by the pro-oxidant 2-methyl-1,4-naphtoquinone with a K(i) dependent on quinone concentration. L-Deprenyl also inhibits the collapse of membrane potential, cation efflux, pyridine nucleotide oxidation and cytochrome c release, all events which accompany the osmotic change and are typical of membrane permeability transition induction, thus emphasizing the inhibitory effect of the drug on this phenomenon. Results show that this inhibition is not due to the effect of L-deprenyl on monoamine oxidase activity but is most likely due to a direct interaction of the drug with the pore forming structures. It is here proposed that L-deprenyl, being a propargylamine, at physiological pH has a protonated amino group able to interact with critical aromatic or anionic amino acidic residues. As a consequence, the opening of the transition pore is prevented. These results indicate a more generalized protective effect of L-deprenyl on mitochondrial functions, involving the inhibition of membrane permeability transition induced not only by the oxidation of substrates of MAO B, but also by pro-oxidant agents such as 2-methyl-1,4-naphtoquinone, which does not involve MAO B activity.
De Marchi
Umberto
U
Dipartimento di Scienze Biomediche Sperimentali, Università di Padova, Padua, Italy.
Pietrangeli
Paola
P
Marcocci
Lucia
L
Mondovì
Bruno
B
Toninello
Antonio
A
D000818:Animals; D004347:Drug Interactions; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012642:Selegiline / Q000494:pharmacology*; D024483:Vitamin K 3 / Q000494:pharmacology*
D008996:Monoamine Oxidase Inhibitors; D017382:Reactive Oxygen Species; D012642:Selegiline; D024483:Vitamin K 3