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Action of diethylstilbestrol and related compounds on the metabolism of rat liver mitochondria

Authors
Journal
Archives of Biochemistry and Biophysics
0003-9861
Publisher
Elsevier
Publication Date
Volume
117
Issue
3
Identifiers
DOI: 10.1016/0003-9861(66)90098-1
Disciplines
  • Biology

Abstract

Abstract The artificial estrogens stilbestrol, dienestrol, and hexestrol inhibit the oxidation of l-malate- l-glutamate by phosphorylating rat liver mitochondria in metabolic State 3. The inhibition takes place mostly at the NAD-flavoprotein region of the electron transport chain, as with nonphosphorylating particles. Succinate oxidation is also inhibited in State 3 but relatively higher concentrations of estrogens are required to produce the same inhibition as with the NAD-linked substrates. With succinate or ascorbate-TMPD ( N,N,N′,N′-tetramethyl- p-phenylenediamine) substrates, artificial estrogens uncouple oxidative phosphorylation as shown by the diminution of P:O quotients, the release of oligomycin inhibition, and the release of respiratory control. In State 4, stimulation of succinate oxidation by stilbestrol is lesser when the estrogen is added before succinate. This relative inhibition is counteracted by addition of ATP, and also when amytal or orthophosphate are present during preincubation with stilbestrol. According to the estrogen concentrations required to inhibit electron transfer and respiratory control, the latter effect is of minor metabolic importance. At variance with other typical uncouplers (DNP, dicoumarol), the estrogens relieve the inhibition of energy transfer by phenetylbiguanidine (DBI) much less and do not induce significant activation of latent ATPase activity even in the presence of Mg ++. Estrogens may induce physical changes of mitochondria, as revealed by swelling. However, the alteration of mitochondrial structure does not cause per se the metabolic responses to estrogens since stilbestrol monomethyl ether, a relatively powerful swelling agent, scarcely affects respiration. Unsubstituted phenolic groups are essential for the estrogens metabolic actions because stilbestrol dimethyl ether, stilbestrol dipropionate, and hexestrol dimethyl ether do not affect mitochondrial respiration.

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