Inhibition of mitochondrial succinate oxidation--similarities and differences between N-methylated beta-carbolines and MPP+.

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.

• 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.)

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

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)