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Titolo:
STUDIES ON THE CHARACTERIZATION OF THE INHIBITORY MECHANISM OF 4'-ALKYLATED 1-METHYL-4-PHENYLPYRIDINIUM AND PHENYLPYRIDINE ANALOGS IN MITOCHONDRIA AND ELECTRON-TRANSPORT PARTICLES
Autore:
GLUCK MR; YOUNGSTER SK; RAMSAY RR; SINGER TP; NICKLAS WJ;
Indirizzi:
UNIV MED & DENT NEW JERSEY,ROBERT WOOD JOHNSON MED SCH,DEPT NEUROL,675 HOES LANE PISCATAWAY NJ 08854 UNIV MED & DENT NEW JERSEY,ROBERT WOOD JOHNSON MED SCH,DEPT NEUROL PISCATAWAY NJ 08854 UNIV CALIF SAN FRANCISCO,DEPT BIOCHEM BIOPHYS SAN FRANCISCO CA 94143 UNIV CALIF SAN FRANCISCO,DEPT PHARM SAN FRANCISCO CA 94143 VET ADM MED CTR,DIV MOLEC BIOL SAN FRANCISCO CA 94121
Titolo Testata:
Journal of neurochemistry
fascicolo: 2, volume: 63, anno: 1994,
pagine: 655 - 661
SICI:
0022-3042(1994)63:2<655:SOTCOT>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
DOPAMINERGIC NEUROTOXIN 1-METHYL-4-PHENYLPYRIDINIUM; PARKINSONS-DISEASE; NADH DEHYDROGENASE; RESPIRATORY-CHAIN; BINDING-SITE; ION MPP+; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE; METABOLITE; OXIDATION; MPTP;
Keywords:
1-METHYL-4-PHENYLPYRIDINIUM ION; TETRAPHENYLBORON ANION; MITOCHONDRIA; ELECTRON TRANSPORT PARTICLES; NADH DEHYDROGENASE; PARKINSONS DISEASE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
30
Recensione:
Indirizzi per estratti:
Citazione:
M.R. Gluck et al., "STUDIES ON THE CHARACTERIZATION OF THE INHIBITORY MECHANISM OF 4'-ALKYLATED 1-METHYL-4-PHENYLPYRIDINIUM AND PHENYLPYRIDINE ANALOGS IN MITOCHONDRIA AND ELECTRON-TRANSPORT PARTICLES", Journal of neurochemistry, 63(2), 1994, pp. 655-661

Abstract

1-Methyl-4-phenylpyridinium (MPP(+)), the toxic agent in MPTP-induceddopaminergic 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 IC50 values that ranged from 0.5 to 110 mu M and from 1.6 to 3,300 mu M in mitochondria and electron transport particles (ETPs), respectively. The IC50 values of corresponding 4'-alkylated phenylpyridine derivatives to inhibit NADH-linked oxidation ranged from 10 to 205 mu M in mitochondria and from 1.7 to 142 mu 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 similar to600-fold, versus only a 36-fold, increase in the ICS, 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 complexI, 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 15/07/20 alle ore 03:04:12