Nitrofurantoin inhibition of mouse liver mitochondrial respiration involving NAD-linked substrates

In our study, nitrofurantoin (NF) and nitrofurazone (NZ) inhibited respiration of isolated mouse (C57B/6J, adult, male) liver mitochondria. Other aromatic nitro compounds, nitroimidazole, metronidazole, and p-nitrobenzoic acid, did not have any significant effect. The primary site of activity for NF...

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Published inToxicology and applied pharmacology Vol. 84; no. 3; p. 493
Main Authors Lim, L O, Bortell, R, Neims, A H
Format Journal Article
LanguageEnglish
Published United States 01.07.1986
Subjects
Animals
Catalase - pharmacology
In Vitro Techniques
Male
Mice
Mice, Inbred C57BL
Mitochondria, Liver - drug effects
Mitochondria, Liver - metabolism
Nitro Compounds - pharmacology
Nitrofurantoin - pharmacology
Oxidation-Reduction
Oxidative Phosphorylation
Oxygen Consumption - drug effects
Substrate Specificity
Superoxide Dismutase - pharmacology
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Summary:In our study, nitrofurantoin (NF) and nitrofurazone (NZ) inhibited respiration of isolated mouse (C57B/6J, adult, male) liver mitochondria. Other aromatic nitro compounds, nitroimidazole, metronidazole, and p-nitrobenzoic acid, did not have any significant effect. The primary site of activity for NF was complex I NADH-ubiquinone oxidoreductase mediated respiration, since only complex I substrates, glutamate, beta-hydroxybutyrate, and alpha-ketoglutarate-mediated respiration were decreased. Respiration supported by succinate, a complex II substrate, was not affected by any of the compounds. NF at a concentration of 50 microM decreased state 3 and dinitrophenol-uncoupled respiration to 28 +/- 1 and 25 +/- 5% of control, respectively, of mitochondria oxidizing glutamate. Studies with mitoplasts oxidizing glutamate showed that NF inhibited both state 3 and 4 respiration. The inhibition of state 3 was prevented by the simultaneous addition of superoxide dismutase (240 micrograms/ml) and catalase (200 micrograms/ml). These results suggest that the mitochondrion, in particular complex I of the electron transport system, is a target for NF toxicity. The effect on respiration may be mediated by NF redox cycling and the generation of reactive oxygen intermediates resulting in the interference of electron flow.
ISSN:0041-008X
DOI:10.1016/0041-008X(86)90254-1