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Inhibitory effect of nicotinamide to paraquat toxicity and the reaction site on complex I
1Department of Environmental Medicine, Shimane Medical University, Japan.
Abstract:
The inhibitory effect and mechanism of action of nicotinamide to paraquat toxicity were studied in male Sprague-Dawley rats. Proteins of submitochondrial particles (SMP), especially of mol. wt. 25-30 kDa, in rat lungs were destroyed by paraquat radicals, and aggregated protein bands approximately 100 kDa were observed by polyacrylamide electrophoresis. The competitive inhibition effects were observed of nicotinamide on NADH oxidation by paraquat via SMP in rat lungs and the Ki was 9.3 mM. The inhibitory effects of nicotinamide on lipid peroxidation by paraquat with rat lung and liver SMP were verified. The times of occurrence of dyspnea and death in rats after paraquat exposure were delayed by nicotinamide administration. The activity of NADH: ubiquinone reaction of NADH:ubiquinone oxidoreductase (complex I) in rat lung was reduced 24 h after paraquat exposure, and was protected by nicotinamide. The activity of NADH:ferricyanide reaction of complex I was, however, reduced by administration not only of paraquat but also nicotinamide. These results imply that nicotinamide is inhibitory to paraquat toxicity. Nicotinamide, paraquat, and ferricyanide may react at overlapping sites on complex I.
Insights
Nicotinamide (NAM) inhibits paraquat (PQ) toxicity by protecting mitochondrial proteins and delaying adverse effects like death. NAM competitively inhibits paraquat
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- Paraquat (PQ) is a herbicide causing significant oxidative stress and cellular damage.
- Mitochondrial dysfunction, particularly involving Complex I, is implicated in paraquat toxicity.
- Nicotinamide (NAM), a form of Vitamin B3, has potential protective properties against oxidative damage.
Purpose of the Study:
- To investigate the inhibitory effect and mechanism of action of nicotinamide against paraquat toxicity.
- To determine if nicotinamide can protect against paraquat-induced damage to mitochondrial proteins and cellular functions.
- To explore the interaction between nicotinamide, paraquat, and mitochondrial complex I.
Main Methods:
- Studied the effects of paraquat and nicotinamide on submitochondrial particles (SMP) from rat lungs and livers.
- Utilized polyacrylamide electrophoresis to analyze protein changes.
- Assessed enzyme activities, including NADH oxidation and NADH:ubiquinone oxidoreductase (Complex I) activity.
- Observed the effects of paraquat and nicotinamide administration on rat survival and respiratory distress.
Main Results:
- Paraquat radicals destroyed specific proteins (25-30 kDa) in lung SMP and formed aggregated bands (~100 kDa).
- Nicotinamide competitively inhibited paraquat's effect on NADH oxidation by SMP (Ki = 9.3 mM) and suppressed lipid peroxidation.
- Nicotinamide administration delayed the onset of dyspnea and death in paraquat-exposed rats and protected Complex I activity in lung mitochondria.
Conclusions:
- Nicotinamide exhibits significant inhibitory effects against paraquat toxicity.
- Nicotinamide protects against paraquat-induced mitochondrial damage and oxidative stress.
- The findings suggest a potential interaction between nicotinamide, paraquat, and Complex I at overlapping sites.