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