Mechanism of nitrofurantoin toxicity and oxidative stress in mitochondria.
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.
Carbonera
D
D
C.N.R. Unit for Physiology of Mitochondria, University of Padova, Italy.
Angrilli
A
A
Azzone
G F
GF
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D003958:Diamide / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D009582:Nitrofurantoin / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D010710:Phosphates / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D051381:Rats
D010710:Phosphates; D003958:Diamide; D009582:Nitrofurantoin; D006861:Hydrogen Peroxide; D011188:Potassium; D002118:Calcium