Oxidative Uncoupling agents

Figure 12-8. Principles of the chemiosmotic theory of oxidative phosphorylation. The main proton circuit is created by the coupling of oxidation in the respiratory chain to proton translocation from the inside to the outside of the membrane, driven by the respiratory chain complexes I, III, and IV, each of which acts as a protonpump. Q, ubiquinone C, cytochrome c F Fq, protein subunits which utilize energy from the proton gradient to promote phosphorylation. Uncoupling agents such as dinitrophenol allow leakage of H" across the membrane, thus collapsing the electrochemical proton gradient. Oligomycin specifically blocks conduction of H" through Fq.

Oxidative Phosphorylation. Oxidative phosphorylation, that is the production of ATP during the passage of electrons down the terminal electron transport chain, may be disrupted in two distinct ways. Compounds that divorce the process of electron transport and the phosphorylation of ADP are termed uncoupling agents. They permit NADH and succinate to be oxidised via the electron transport chain without the production of ATP and are lethal. Oxidative phosphorylation may also be inhibited directly, thus preventing the oxidation of NADH and succinate. Several products are available that exploit these modes of action. Characteristically, they have wide activity spectra that span major disciplines of pesticide use. 

The effect of nonfatal injuries such as a 2-hour period of bilateral hind-limb ischemia or a full-thickness scald of 20% of skin surface on the LDso of DNOC and its hyperthermic effect were evaluated in male rats (Stoner 1969). The intraperitoneal LDs° of DNOC was significantly (p<0.001) reduced from 24.8 to 26.2 mg/kg to 14 mg/kg DNOC when DNOC was given 1.5- 24 hours after either type of nonfatal injury. The authors concluded that the toxicity of DNOC was increased by previous trauma. These investigators proposed that this interaction was associated with sequential blocking of the tricarboxylic acid cycle with inhibition of citrate synthetase reaction during the early part of the response to the injury. Because DNOC acts as an uncoupler of oxidative phosphorylation, less ATP is produced. Therefore, the effects of trauma will be enhanced by an uncoupling agent such as DNOC. 

Certain chemical substances have been known for many years to uncouple oxidation from phosphorylation and to inhibit active transport, and for this reason they are named uncoupling agents. They are believed to act by rendering the membrane permeable to protons, hence short-circuiting the potential gradient or proton-motive force. 

If the inner mitochondrial membrane is damaged such that it no longer provides a barrier to the movement of protons, then the proton electrochemical gradient is destroyed and oxidative phosphorylation will not occur. Uncoupling agents, such as 2,4-dinitrophenol, which permeabilize the inner mitochondrial membrane to protons, also inhibits oxidative phosphorylation for the same reason. 

The observed alterations possibly inOience lipid-protein relation and thns alter the activity of the enzymes associated with the membrane. Indeed, IW lesnlts in a decrease of the maximal rates of NAD-dependent substrates oxidation. The rate of the pair glutamate + malate oxidation in the presence of uncoupling agent (FCCP) drops from 70.0 4.6 down to 48.9 3.2 ng oxygen atom/mg of protein min and the respiratory control rate (RCR) decreases from 2.27 0.1 to 1.7 0.2 (Table 2). 

Another theory was offered to explain the mode of action of these compounds when it was noted that dicoumarol is a potent uncoupling agent of oxidative phosphorylation [363]. The antibacterial action of the 3-acetyl-4-hydroxycoumarin may be associated with its uncoupling action [364, 365]. Similarly, a relationship has been suggested between the anticoagulant activity of dicoumarol and related compounds and their uncoupling activity [366]. 

DNP is an uncoupling agent and uncouples electron transport from oxidative phosphoryiation. It does this when the dinitrophe-nate anion accepts a proton to form dinitrophenoi, which is lipid soluble, and diffuses across the mitochondrial inner membrane. When... 

Changes in oxidative phosphorylation seem to be more closely related to the primary site of action of the thyroid hormones. Thyroxine uncouples oxidative phosphorylation in mitochondria and causes the energy released during oxidation of the Krebs cycle intermediates to be less efficiently used for ATP synthesis. A direct effect of thyroxine on oxidative phosphorylation would conveniently explain many metabolic effects of thyroxine, but it would leave unexplained the beneficial effects of small amounts of thyroxine. A direct effect on oxidative phosphorylation is also inconsistent with the fact that uncoupling agents are unable to correct hypothyroidism. 

Mitochondrial studies have uncovered a whole group of substances, e.g., 2,4-dinitrophenol, gramicidin, and aureomycin, which can dissociate esterification of inorganic phosphate from the oxidation process. These substances have become known as uncoupling agents. There is some evidence that they uncouple by dephosphorylating the primary acceptor complex before the phosphoryl group can be transferred to ADP. ... 

Various substances inhibit the formation of ATP without interrupting the transport of electrons. This phenomenon is called uncoupling of oxidative phosphorylation." The most frequently used substance is dinitrophenol. Dicumarol, the ants o-nist of vitamin K, also is an uncoupling agent. A biologic regulation of couplii is probable the biologic uncoupler, however, is still not known. 

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