Brain mitochondria catalyze the oxidation of 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxyli c acid (DHBT-1) to intermediates that irreversibly inhibit complex I and scavenge glutathione: potential relevance to the pathogenesis of Parkinson's disease.
We have proposed that a very early step in the pathogenesis of idiopathic Parkinson's disease is the elevated translocation of L-cysteine into neuromelanin-pigmented dopaminergic neurons in the substantia nigra. This influx of L-cysteine was proposed to divert the normal neuromelanin pathway by scavenging dopamine-o-quinone, formed by autoxidation of cytoplasmic dopamine, to give initially 5-S-cysteinyldopamine, which is further oxidized to 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1). In a recent report, it was demonstrated that DHBT-1 evokes inhibition of complex I respiration when incubated with intact rat brain mitochondria and a time-dependent irreversible inhibition of NADH-coenzyme Q1 (CoQ1) reductase when incubated with mitochondrial membranes. In this study, it is established that the time dependence of NADH-CoQ1 reductase inhibition reflects the oxidation of DHBT-1, catalyzed by an unknown constituent of the inner mitochondrial membrane, to an o-quinone imine intermediate that rearranges to 7-(2-aminoethyl)-5-hydroxy-1,4-benzothiazine-3-carboxylic acid (BT-1) and decarboxylates to 7-(2-aminoethyl)-5-hydroxy-1,4-benzothiazine (BT-2), which are further catalytically oxidized to o-quinone imine intermediates. The electrophilic o-quinone imine intermediates formed in these mitochondria-catalyzed oxidations of DHBT-1, BT-1, and BT-2 are proposed to bind covalently to key sulfhydryl residues at the complex I site, thus evoking irreversible inhibition of NADH-CoQ1 reductase. Evidence for this mechanism derives from the fact that greater than equimolar concentrations of glutathione completely block inhibition of NADH-CoQ1 reductase by DHBT-1, BT-1, and BT-2 by scavenging their electrophilic o-quinone imine metabolites to form glutathionyl conjugates. The results of this investigation may provide insights into the irreversible loss of glutathione and decreased mitochondrial complex I activity, which are both anatomically specific to the substantia nigra and exclusive to Parkinson's disease.
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Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019, USA.
Shen
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Dryhurst
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D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002384:Catalysis; D004298:Dopamine / Q000031:analogs & derivatives / Q000494:pharmacology; D042967:Electron Transport Complex I; D004791:Enzyme Inhibitors / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005978:Glutathione / Q000037:antagonists & inhibitors* / Q000502:physiology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013843:Thiazines / Q000378:metabolism* / Q000494:pharmacology
C108502:7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid; C115529:7-(2-aminoethyl)-5-hydroxy-1,4-benzothiazine; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D013843:Thiazines; C047408:5-S-cysteinyldopamine; D009247:NADH, NADPH Oxidoreductases; D016660:NAD(P)H Dehydrogenase (Quinone); D042967:Electron Transport Complex I; D005978:Glutathione; D004298:Dopamine