Mechanism of cytotoxicity of paraquat. I. NADH oxidation and paraquat radical formation via complex I.
The mechanism of cytotoxicity by paraquat was studied focusing attention on its effect on the mitochondrial electron transport system. Paraquat inhibited both mitochondrial and cytoplasmic malate dehydrogenase activities. NADH oxidation was verified in NADH: ubiquinone oxidoreductase (complex I) reaction mixture in which paraquat was an only electron acceptor, and paraquat radical formation was observed as turning blue of the reaction mixture. A kinetic characteristic of this enzyme reaction was that Km was so high as 4.1 mM. The maximum reaction velocity was defined in the range over pH 9. NADH autoxidation with complex I, but without paraquat, was not observed in any pH range. The maximum reaction velocity of the NADH autoxidation by paraquat without complex I was observed in pH 8.5, but the figure was so small as to be negligible. With these results, we propose the hypothesis that paraquat does not promote the autoxidation with complex I, but accepts electrons via complex I to induce paraquat radical formation.
Fukushima
T
T
Department of Environmental Medicine, Shimane Medical University, Japan.
Yamada
K
K
Isobe
A
A
Shiwaku
K
K
Yamane
Y
Y
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004579:Electron Transport; D005609:Free Radicals; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D010084:Oxidation-Reduction; D010269:Paraquat / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D005609:Free Radicals; D009243:NAD; D016660:NAD(P)H Dehydrogenase (Quinone); D010269:Paraquat