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Mitochondria toxicity of antihyperlipidemic agents bezafibrate and fenofibrate

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Abstract

Aim

Fenofibrate (FF) is known to block ATP synthesis in mitochondria by inhibiting electron transport at NADH–ubiquinone (UQ) oxidoreductase (complex I) in the respiratory chain.

Methods

Toxicity to mitochondria of bezafibrate (BF) was compared with that of FF, focusing exclusively on their effects on impairment of the electron-transport and energy-transfer systems in oxidative phosphorylation, by experiments with isolated rat liver mitochondria and submitochondrial particles (SMP).

Results

FF and BF had an uncoupling effect, enhancing ATP hydrolytic activity (latent ATPase) in mitochondria. DNP-stimulated ATPase activity was not suppressed by either agent, indicating no interference with the energy-transfer system. Both reagents inhibited NAD-linked respiration but did not affect succinate-linked respiration, indicating specific inhibition of electron-transport activity in complex I. NADH oxidase in SMP was strongly inhibited by FF, and activity was recovered by treatment with tetramethyl-p-phenylenediamine, indicating that the site of inhibition is not located at the NADH dehydrogenase portion but at the UQ site in complex I. Uncoupling and electron-transport inhibition by BF were noticeably weaker than those by FF.

Conclusions

From these results it was concluded that BF and FF were toxic to mitochondria through the dual actions of an uncoupling effect and electron-transport inhibition. The toxicity of BF to mitochondrial function was found to be noticeably weaker than that of FF, implying that BF might be much less toxic than FF for long term in-vivo use as an antihyperlipidemic agent.

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Authors and Affiliations

  1. Department of General Internal Medicine, Gifu Municipal Hospital, Gifu, Japan

    K. Yamada, T. Ikeda & K. Taguchi

  2. Department of Health and Nutrition, Kagoshima Immaculate Heart University, Satsuma Sendai, Japan

    K. Tsunoda

  3. Department of General Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan

    K. Kawai, K. Kajita, H. Morita & T. Ishizuka

Authors
  1. K. Yamada
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  2. K. Tsunoda
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  3. K. Kawai
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  4. T. Ikeda
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  5. K. Taguchi
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  6. K. Kajita
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  7. H. Morita
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  8. T. Ishizuka
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Corresponding author

Correspondence to T. Ishizuka.

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Yamada, K., Tsunoda, K., Kawai, K. et al. Mitochondria toxicity of antihyperlipidemic agents bezafibrate and fenofibrate. Diabetol Int 4, 126–131 (2013). https://doi.org/10.1007/s13340-012-0104-9

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  • DOI: https://doi.org/10.1007/s13340-012-0104-9

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