Oxidative uncouplers

Stress Heat-fever Heavy metals Oxidant injury Oxidative uncouplers Ischemia... 

Mitochondria do three things oxidize substrates, consume oxygen, and make ATP. Uncouplers prevent the synthesis of ATP but do not inhibit oxygen consumption or substrate oxidation. Uncouplers work by destroying the pH gradient. The classic uncoupler is dinitrophenol (DNP). This phenol is a relatively strong acid and exists as the phenol and the phenolate anion. 

Phosphoric-carboxylic anhydride, see Carboxylic-phosphoric anhydride Phosphorus tribromide, 39 Phosphorylase b, 241, 293, 310-318 activation, 293 Phosphorylation cd nucleosides, 324,325 oxidative, uncoupling, 83 Phosphoryl azide, 78 Phosphorylazide diesters, 87 of-Phosphoryl nitrenes, 78... 

Inhibition of oxidative phosphorylation (e.g., by trisubstituted tin fungicides) results in limited oxygen uptake with lower ATP formation. The effects of fatigue and weakness are similar to the effects of oxidative uncouplers, but there is no fever. 

Sulflutamid or A/-ethylpetfluotoctanesulfonamide [4151 -50-2] CgF yS02NHC2H, is a slow-acting stomach poison used in baits for the control of ants and cockroaches. It acts as an uncoupler of oxidative phosphorylation. 

The modes of action for niclosamide are interference with respiration and blockade of glucose uptake. It uncouples oxidative phosphorylation in both mammalian and taenioid mitochondria (22,23), inhibiting the anaerobic incorporation of inorganic phosphate into adenosine triphosphate (ATP). Tapeworms are very sensitive to niclosamide because they depend on the anaerobic metaboHsm of carbohydrates as their major source of energy. Niclosamide has selective toxicity for the parasites as compared with the host because Httle niclosamide is absorbed from the gastrointestinal tract. Adverse effects are uncommon, except for occasional gastrointestinal upset. 

For type 3 processes, growth and metabolic activity reach a maximum early in the batch process cycle (Figure 3.1) and it is not until a later stage, when oxidative activity is low, that maximum desired product formation occurs. The stoichiometric descriptions for both type 3 and 4 processes depend upon the particular substrates and products involved. In the main, product formation in these processes is completely uncoupled from cell growth and dictated by kinetic regulation and activity of cells. 

Forstermann U (2006) Janus-faced role of endothelial NO synthase in vascular disease - Uncoupling of NADPH oxidation from NO synthesis and its pharmacological reversal. Biol Chem 387 1521-1533... 

Many inhibitors of substrate oxidations, substrate transport, electron transport, and ATP synthesis are known including many well-known toxins (see Sherratt, 1981 Harold, 1986 Nicholls and Ferguson, 1992). These are not discussed here except to mention specific uncouplers of oxidative phosphorylation. Classic uncouplers such as 2,4-dinitrophenol have protonated and unprotonated forms, both of which are lipid soluble and cross the inner mitochondrial membrane discharging the proton gradient. This prevents ATP synthesis and stimulates respiration. 

Clofibrate causes a necrotizing myopathy, particularly in patients with renal failure, nephrotic syndrome or hypothyroidism. The myopathy is painful and myokymia of unknown origin is sometimes present. The mechanism of damage is not known, but p-chlorophenol is a major metabolite of clofibrate and p-chlorophe-nol is a particularly potent uncoupler of cellular oxidative phosphorylation and disrupts the fluidity of lipid membranes. Muscle damage is repaired rapidly on the cessation of treatment. 

In addition to the foregoing, three further examples in this list (numbers 5-7) deserve consideration. These are (5) interaction of endocrine disrupters with the estrogen receptor, (6) the action of uncouplers of oxidative phosphorylation, and (7) mechanisms of oxidative stress. Until now only the first is well represented by biomarker assays that have been employed in ecotoxicology. 

Uncouplers of oxidative phosphorylation Compounds that uncouple oxidative phosphorylatiou from electron transport in the inner mitochondrial membrane. Most are weak lipophilic acids that can run down the proton gradient across this membrane. 

Uncouples oxidative DNOC and certain other Hassall (1990), TJ 0)... 

Much information about the respiratory chain has been obtained by the use of inhibitors, and, conversely, this has provided knowledge about the mechanism of action of several poisons (Figure 12-7). They may be classified as inhibitors of the respiratory chain, inhibitors of oxidative phosphorylation, and uncouplers of oxidative phosphorylation. 

The action of uncouplers is to dissociate oxidation in the respiratory chain from phosphorylation. These compounds are toxic in vivo, causing respiration to become uncontrolled, since the rate is no longer limited by the concentration of ADP or Pj. The uncoupler that has been used most frequently is 2,4-dinitrophenol, but other compounds act in a similar manner. The antibiotic oligomycin completely blocks oxidation and phosphorylation by acting on a step in phosphorylation (Figures 12-7 and 12-8). 

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.

Uncouplers (eg, dinitrophenol) are amphipathic (Chapter 14) and increase the petmeabihty of the lipoid inner mitochondrial membrane to protons (Figure 12—8), thus teducing the electtochemical potential and shott-citcuiting the ATP synthase. In this way, oxidation can proceed without phosphotylation. 

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