Abstract |
N-Methylated beta-carbolinium compounds (N-Me-BCs), including 2-N-methyl and 2,9-N,N-dimethyl analogs, structural analogs of 1-methyl-4-phenylpyridinium (MPP+), may be endogenously bioactivated, MPP(+)-like toxins, capable of inducing parkinsonism. Both MPP+ and selected N-Me-BCs inhibit NADH-linked mitochondrial respiration (Complex I). We now show that both also inhibit succinate-supported (Complex II) respiration, the greatest inhibition (80%) being seen for 2,9-dimethylharmanium. Complex I inhibition occurs at MPP+ concentrations (IC50 = 0.17 mM) about one order of magnitude lower than Complex II inhibition (greater than 1.2 mM). In contrast, Complex I and Complex II inhibition by the N-Me-BCs tested occurred at similar concentrations (I, 0.1 mM; II, 0.25 mM) and concentrations similar to Complex I inhibition by MPP+. 2,9-N,N-Dimethyl-BCs, which are the permanently charged BC analogs of MPP+, show inhibitory characteristics similar to MPP+: slow onset of inhibition, potentiation by TPB, and reversal by DNP. The fact that succinate oxidation cannot bypass the Complex II inhibition by N-Me-BCs could enhance any chronic neurotoxicity of N-Me-BCs.
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Authors | J Z Fields, R R Albores, E J Neafsey, M A Collins |
Journal | Archives of biochemistry and biophysics
(Arch Biochem Biophys)
Vol. 294
Issue 2
Pg. 539-43
(May 01 1992)
ISSN: 0003-9861 [Print] United States |
PMID | 1314543
(Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Carbolines
- Multienzyme Complexes
- Succinates
- Oxidoreductases
- Electron Transport Complex II
- Succinate Dehydrogenase
- NAD(P)H Dehydrogenase (Quinone)
- Electron Transport Complex III
- 1-Methyl-4-phenylpyridinium
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Topics |
- 1-Methyl-4-phenylpyridinium
(pharmacology)
- Animals
- Carbolines
(pharmacology)
- Electron Transport Complex II
- Electron Transport Complex III
(antagonists & inhibitors)
- Female
- Kinetics
- Mitochondria, Liver
(drug effects, metabolism)
- Molecular Structure
- Multienzyme Complexes
(antagonists & inhibitors)
- NAD(P)H Dehydrogenase (Quinone)
(antagonists & inhibitors)
- Oxidoreductases
(antagonists & inhibitors)
- Oxygen Consumption
(drug effects)
- Rats
- Rats, Inbred Strains
- Structure-Activity Relationship
- Succinate Dehydrogenase
(antagonists & inhibitors)
- Succinates
(metabolism)
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