Inhibition of electron and energy transfer in mitochondria by 19-nor-ethynyltestosterone acetate

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Abstract

19-Nor-ethynyltestosterone acetate (NEA) is an effective inhibitor of mitochondrial respiration in the vicinity of the NADH dehydrogenase flavoprotein. At this site, half-maximal inhibitory values allow the establishment of NEA as a more potent inhibitor than barbiturates and guanidines but less effective than piericidin and rotenone. NEA inhibits both electron and energy transfer in mitochondria and submitochondrial particles, as shown by (a) the higher effectiveness on reversed (energy-dependent) than on forward electron transfer and (b) the partial release of NEA inhibition by uncouplers. Inhibition of energy transfer prevails at the lower (< 20 μm) NEA concentration and is reversed by serum albumin, while inhibition of electron transfer prevails at the higher (> 30 μm) NEA concentrations and is apparently irreversible. In contrast to typical inhibitors of energy transfer, NEA releases latent mitochondrial ATPase and does not inhibit the DNP-stimulated ATPase activity. Addition of NEA to mitochondria respiring NAD-linked substrates shifts the redox level of pyridine nucleotide toward the reduced state while the reverse occurs with cytochrome b and ubiquinone. The effect of NEA on absorbancy levels at the flavo-protein spectral region, with both mitochondrial and submitochondrial preparations, can be explained in terms of interaction of NEA with a steroid-sensitive site located on the oxygen side of the mitochondrial NADH flavoprotein, very close or partly superimposed upon the rotenone site. Another flavoprotein, the succinate dehydrogenase, appears to be located between the NEA-sensitive site and the cytochrome chain. As with rotenone, barbiturates and piericidin, NEA inhibition would involve a lipid component of the respiratory chain.

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  • Cited by (0)

    Aided by grants from Consejo Nacional de Investigaciones Científicas y Técnicas, The Jane Coffin Childs Fund for Medical Research, and the United States Air Force Office under Grant AFOSR-68-1395, monitored by the Air Force Office of Scientific Research, Office of Aerospace Research.

    2

    Research Fellow, Consejo Nacional de Investigaciones Cinetíficas y Técnicas, Argentina.

    3

    Present address: Johnson Research Foundation, University of Pennsylvania, Philadelphia, Pennsylvania 19104.

    4

    Member of Investigator Career, Consejo Nacional de Investigaciones Científicas y Técnicas Argentina.

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