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Mechanism of nitrofurantoin toxicity and oxidative stress in mitochondria
D Carbonera1, A Angrilli, G F Azzone
1C.N.R. Unit for Physiology of Mitochondria, University of Padova, Italy.
Abstract:
5-Nitrofuran derivatives change the inner mitochondrial membrane permeability as indicated by the transmembrane potential, the rate of spontaneous K+ efflux and the basal respiratory rate: (a) at low concentrations nitrofurantoin prevents the increase of inner membrane permeability due to hydroperoxides or to diamide; (b) at higher concentrations or after longer times of incubation, nitrofurantoin enhances the membrane damage due to hydroperoxides or to diamide; the damage due Ca2+ plus Pi is enhanced by nitrofurantoin at all concentrations; (c) higher nitrofurantoin concentrations cause membrane damage independently of the presence of hydroperoxides or of diamide. The effect of nitrofurantoin is cancelled by the addition of free-radical scavengers. The above effects of nitrofurantoin are compatible with the observations of Mason and colleagues that nitrofurantoin is reduced by a NADPH nitroreductase to a nitro anion radical which can then undergo subsequent reactions, among which are (a) initiation of a free-radical reaction chain and (b) reduction of hydroperoxides and diamide.
Insights
Nitrofurantoin alters mitochondrial membrane permeability by affecting ion transport and respiration. Its effects are concentration-dependent and involve free radical mechanisms, potentially explaining its biological activity.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Mitochondrial inner membrane permeability is crucial for cellular energy production.
- Dysregulation of mitochondrial function is implicated in various pathologies.
- 5-Nitrofurans are a class of compounds with known antimicrobial properties.
Purpose of the Study:
- To investigate the effects of nitrofurantoin on mitochondrial inner membrane permeability.
- To elucidate the mechanisms underlying nitrofurantoin-induced mitochondrial dysfunction.
- To explore the role of free radicals in nitrofurantoin's action.
Main Methods:
- Assessment of mitochondrial transmembrane potential.
- Measurement of K+ efflux rate.
- Determination of basal respiratory rate.
- Evaluation of nitrofurantoin's interaction with hydroperoxides and diamide.
- Inclusion of free-radical scavengers to assess mechanism.
Main Results:
- Nitrofurantoin modulates inner mitochondrial membrane permeability in a concentration- and time-dependent manner.
- At low concentrations, it protects against hydroperoxide- or diamide-induced damage; at higher concentrations, it enhances this damage.
- Nitrofurantoin potentiates Ca2+ plus Pi-induced membrane damage at all concentrations.
- High nitrofurantoin concentrations induce membrane damage independently of external agents.
- Free-radical scavengers abolish the observed effects, suggesting a free-radical mechanism.
Conclusions:
- Nitrofurantoin's effects on mitochondrial membranes are mediated by free radical generation, initiated by its reduction to a nitro anion radical.
- These findings align with the known redox cycling of nitrofurans and provide insight into their mechanism of action.
- The study highlights the complex interplay between nitrofurantoin, oxidative stress, and mitochondrial integrity.