Uncoupling, of phosphorylations

Acute toxicity to aquatic species can be rationalized mechanistically by one of two types of interactions nonspecific mechanisms (called narcosis) or specific mechanisms. The latter involves specific interactions, such as covalent electrophilic reactions with biological macromolecules, or specific noncovalent interactions that cause toxicity, such as uncoupling of phosphorylative oxidation, among others. Most chemicals that are toxic to aquatic organisms are narcotic. Some have both narcotic and specific mechanisms. A narcotic chemical enters the cellular membranes of the organism and, by its mere presence, causes perturbations in the membranes to the extent that alterations in the function of the membranes occur, resulting in toxicity. 

Uncoupling of phosphorylation from electron transfer FCCP DNP Hydrophobic proton carriers... 

The A/Xh+ can be generated by light-induced or dark electron transport, as well as by hydrolysis of ATP, GTP or PPj [7,8], The rates of the ATP- and PP -driven reactions are about 70 and 56% of the light-driven reaction, respectively. The addition of both ATP and PPj stimulates the rate more than either alone, and gives a rate almost as high as light. The PP-driven reaction is inhibited by uncouplers of phosphorylation but not by electron-transport inhibitors or oligomycin. The stoicheiometries of ATP and PP hydrolyzed to NADP reduced are 1 and 10, respectively. 

Needleman attempted to correlate the antianginal activity of nitrates with their ability to produce loss of respiratory control in mitochondria. He suggests that nitroglycerin exerts its effect by reacting with SH groups within the mitochondria, thereby causing an uncoupling of phosphorylation. ... 

The mechanism of action of the phenothiazines is still not definitely known. They tend to block important effector substances such as acetylcholine, epinephrine, and histamine. The phenothiazines produce uncoupling of phosphorylation from oxidation. They appear to act at all steps along the electron transport chain. Cytochrome oxidase, succinoxidase, and adenosine triphosphatase are inhibited. Some data indicate that the phenothiazines may decrease the permeability of storage granules for brain amines. 

Nitrogenase induction was prevented by the protein-biosynthesis inhibitor, chloramphenicol, and nitrogenase activity by carbonyl cyanide-m-chloro-phenylhydrazone (CCCP), an uncoupler of phosphorylation (Weisshaar,... 

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. 

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. 

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. 

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