Inhibition of mitochondrial respiration by progesterone and an azasteroid

Abstract

The effect of progesterone and 4-dimethylaminoethyl-4-aza-5-cholester-3-one methiodide (azasteroid) on DPNH and succinate oxidation in submitochondrial particles has been studied. Progesterone inhibited DPNH oxidation by oxygen or ubiquinone-6 equally. The inhibition by the azasteroid, under the same conditions, was similar, but weaker, compared with inhibition by progesterone. The reoxidation of the flavoprotein reduced by DPNH was inhibited strongly by progesterone in a manner analogous to the effect of rotenone. In addition, cytochromes b and c remained in the partially reduced steady-state condition for a longer time when progesterone was present than in its absence. The results indicate that the primary site of progesterone inhibition is between flavoprotein and ubiquinone. Succinate oxidation also was inhibited, but to a lesser extent, indicating a secondary site of inhibition. Since the oxidation of ascorbate-TMPD (tetramethyl- p-phenylene diamine) was not significantly inhibited by the steroids at these levels, the secondary inhibition site may lie between cytochrome b and cytochrome c. Even higher levels of steroid produced inhibition of oxidation in the cytochrome oxidase region, suggesting a tertiary site of action. Progesterone inhibited ADP-stimulated and dinitrophenol-stimulated respiration equally in intact mitochondria, indicating little or no effect on energy-transfer reactions.