Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation.
We have examined the effects of a variety of classical and atypical neuroleptic drugs on mitochondrial NADH ubiquinone oxido-reductase (complex I) activity. Sagittal slices of mouse brain incubated in vitro with haloperidol (10 nM) showed time- and concentration-dependent inhibition of complex I. Similar concentrations of the pyridinium metabolite of haloperidol (HPP+) failed to inhibit complex I activity in this model; indeed, comparable inhibition was obtained only at a 10000-fold higher concentration of HPP+ (100 microM). Treatment of brain slices with haloperidol resulted in a loss of glutathione (GSH), while pretreatment of slices with GSH and alpha-lipoic acid abolished haloperidol-induced loss of complex I activity. Incubation of mitochondria from haloperidol treated brain slices with the thiol reductant, dithiothreitol, completely regenerated complex I activity demonstrating thiol oxidation as a feasible mechanism of inhibition. In a comparison of different neuroleptic drugs, haloperidol was the most potent inhibitor of complex I, followed by chlorpromazine, fluphenazine and risperidone while the atypical neuroleptic, clozapine (100 microM) did not inhibit complex I activity in mouse brain slices. The present studies support the view that classical neuroleptics such as haloperidol inhibit mitochondrial complex I through oxidative modification of the enzyme complex.
Balijepalli
S
S
Department of Neurochemistry, National Institute of Mental Health and Neurosciences, Bangalore, India.
Boyd
M R
MR
Ravindranath
V
V
D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects; D042963:Electron Transport Complex II; D014450:Electron Transport Complex III / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006220:Haloperidol / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D009097:Multienzyme Complexes / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D008063:Thioctic Acid / Q000378:metabolism
D014150:Antipsychotic Agents; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D013438:Sulfhydryl Compounds; D008063:Thioctic Acid; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D016660:NAD(P)H Dehydrogenase (Quinone); D014450:Electron Transport Complex III; D005978:Glutathione; D006220:Haloperidol