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OtherTOXICOLOGY

The Pyrethroids Permethrin and Cyhalothrin are Potent Inhibitors of the Mitochondrial Complex I

Beat Gassner, Andreas Wüthrich, Günter Scholtysik and Marc Solioz
Journal of Pharmacology and Experimental Therapeutics May 1997, 281 (2) 855-860;
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Andreas Wüthrich
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Günter Scholtysik
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Marc Solioz
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Abstract

The synthetic pyrethroid derivatives permethrin and cyhalothrin are widely used insecticides that are considered to be relatively nontoxic to higher animals. However, a variety of toxic effects on mammals have been reported. We investigated the effect of these drugs on energy coupling by mitochondria and on the activity of the individual respiratory complexes. Using isolated rat liver mitochondria, a concentration-dependent inhibition of glutamate and succinate sustained state 3 respiration was found for both compounds in the micromolar range. The effect of pyrethroids on the activities of the complexes I to V were assessed individually in submitochondrial particles (complex I) and in freeze-thawed mitochondria (complexes II–V). Complex I (EC 1.6.5.3) was found to be the most sensitive link within the electron transport chain. Half-maximal inhibition was observed at 0.73 μM permethrin and 0.57 μM cyhalothrin, respectively, and exhibited sigmoidal inhibition kinetics. Complexes II, III, IV and V (EC 1.3.5.1, 1.10.2.2, 1.9.3.1, 3.6.1.34) were not significantly inhibited by up to 50 μM of these drugs. Thus, our results reveal a mode of action of synthetic pyrethroid insecticides not previously reported.

Footnotes

  • Send reprint requests to: Dr. Marc Solioz, Department of Clinical Pharmacology, Murtenstrasse 35, CH-3010 Berne, Switzerland.

  • ↵1 This work was supported in part by Grant 3200-046804 from the Swiss National Foundation.

  • Abbreviations:
    DCCD
    N,N′-dicyclohexylcarbodiimide
    MOPS
    3-morpholinopropanesulfonic acid
    EDTA
    ethylenediamintetraacidic acid
    EGTA
    ethyleneglycol-bis-(2-aminoethyl)-tetraacetic acid, NADH, nicotinamideadeninedinucleotide
    RQGlutamate
    respiratory quotient with glutamate
    MPTP
    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
    MPP+
    1-methyl-4-phenylpyridinium
    RQ
    respiratory quotient, defined as the ratio of state 3 to state 4 respiration
    DMSO
    dimethylsulfoxide
    • Received September 10, 1996.
    • Accepted January 6, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 281, Issue 2
1 May 1997
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OtherTOXICOLOGY

The Pyrethroids Permethrin and Cyhalothrin are Potent Inhibitors of the Mitochondrial Complex I

Beat Gassner, Andreas Wüthrich, Günter Scholtysik and Marc Solioz
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 855-860;

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OtherTOXICOLOGY

The Pyrethroids Permethrin and Cyhalothrin are Potent Inhibitors of the Mitochondrial Complex I

Beat Gassner, Andreas Wüthrich, Günter Scholtysik and Marc Solioz
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 855-860;
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