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Studies on the Characterization of the Inhibitory Mechanism of 4′‐Alkylated 1‐Methyl‐4‐Phenylpyridinium and Phenylpyridine Analogues in Mitochondria and Electron Transport Particles
Author(s) -
Gluck Martin R.,
Youngster Stephen K.,
Ramsay Rona R.,
Singer Thomas P.,
Nicklas William J.
Publication year - 1994
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1994.63020655.x
Subject(s) - alkylation , chemistry , inhibitory postsynaptic potential , mitochondrion , electron transport chain , mechanism (biology) , electron , biophysics , stereochemistry , biochemistry , biology , neuroscience , physics , catalysis , quantum mechanics
1‐Methyl‐4‐phenylpyridinium (MPP + ), the toxic agent in MPTP‐induced dopaminergic neurotoxicity, is thought to act by inhibiting mitochondrial electron transport at complex I. This study examined this latter action further with a series of 4′‐alkylated analogues of MPP + . These derivatives had IC 50 values that ranged from 0.5 to 110 µ M and from 1.6 to 3,300 µ M in mitochondria and electron transport particles (ETPs), respectively. The IC 50 values of corresponding 4′‐alkylated phenylpyridine derivatives to inhibit NADH‐linked oxidation ranged from 10 to 205 µ M in mitochondria and from 1.7 to 142 µ M in ETPs. The potencies of both classes of inhibitors directly correlated with their ability to partition between 1‐octanol and water. In mitochondria, increased hydrophobicity resulted in greater inhibition of NADH dehydrogenase but a smaller dependence on the transmembrane electrochemical gradient for accumulation of the pyridiniums as evidenced by an ∼600‐fold, versus only a 36‐fold, increase in the IC 50 of MPP + versus 4′‐pentyl‐MPP + , respectively, in the presence of uncoupler. In ETPs, the analogous increase in potencies of the more hydrophobic analogues was also consistent with an inhibitory mechanism that relied on differential partitioning into the lipid environment surrounding NADH dehydrogenase. However, the pyridinium charge must play a major role in explaining the inhibitory mechanism of the pyridiniums because their potencies are much greater than would be predicted based solely on hydrophobicity. For example, in ETPs, 4′‐decyl‐MPP + was nearly 80‐fold more potent than phenylpyridine although the latter compound partitions twice as much into 1‐octanol. In addition, the lipophilic anion TPB − was a more effective potentiator of inhibition by pyridiniums possessing greater hydrophilicity (0–5 carbons), consistent with facilitation of accumulation of these analogues within the membrane phase of complex I, probably via ion pairing. These studies delineate further the mechanisms by which this class of compounds is able to accumulate in mitochondria, inhibit complex I activity, and thereby, effect neurotoxicity.