Uncouplers of oxidative phosphorylation

Part 2 Insecticides and Fun ddes, The Royal Society of Chemistry, 

Tomigahara, N. Isobe, H. Kaneko, I. Nakatsuka, J. Agric. Food Chem. 2000, 

Y Spencer, Guide to the Chemicals Used in Crop Proteaion, publication 1093, Agriculture Canada, Canadian Government Publishing Centre, 

43 United States Environmental Protection Agency, Reregistration Eligibility Decision for Carboxin, document EPA 738-R-04-015, 2004 (http // www.epa.gov/ oppsrrdl/REDs/ 

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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. 

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. 

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. 

R.L. Williamson and R.L. Metcalf, Salicylanilides a new group of active uncouplers of oxidative phosphorylation. Science, 158 (1967) 1694-1695. 

Carbonylcyanide-4-trilluoromethoxyphenylhydrazone is known as a protonophore or uncoupler of oxidative phosphorylation in bioelectrochemistry because it disrupts the tight coupling between electron transport and the ATP synthase. Uncouplers act by dis-... 

Nucleic acids are not the only biomolecules susceptible to damage by carotenoid degradation products. Degradation products of (3-carotene have been shown to induce damage to mitochondrial proteins and lipids (Siems et al., 2002), to inhibit mitochondrial respiration in isolated rat liver mitochondria, and to induce uncoupling of oxidative phosphorylation (Siems et al., 2005). Moreover, it has been demonstrated that the degradation products of (3-carotene, which include various aldehydes, are more potent inhibitors of Na-K ATPase than 4-hydroxynonenal, an aldehydic product of lipid peroxidaton (Siems et al., 2000). 

Terada, H. (1990). Uncouplers of oxidative phosphorylation, Environ. Health Perspect., 87, 213-218. 

Dinitrophenol (1 mM) and potassium cyanide (KCN) (5 mM) are used as uncouplers of oxidative phosphorylation from electron transport (105). 

Aspirin in doses used to treal rheumatoid arthritis can result in uncoupling of oxidative phosphorylation, increased oxygen consumption, depletion of hepatic glycogen, and the pyref c effect of toxic doses of salicylate. Depending on the degree of salicylate intoxication, the symptoms can vary from tinnitus to pronounced CNS and acid-base disturbance. 

Uncoupling of oxidative phosphorylation from respiration in brown adipose tissue and possibly other tissues (e.g. in muscle) (Chapter 9). 

Because rodent populations world-wide were becoming resistant to the widely used Warfarin-type anticoagulant poisons, a search was initiated to find a rodenticide with a different mode of action one that would be effective against these resistant rodents. This search led to the discovery of the toxic nature of a family of diphenyl amines which act as uncouplers of oxidative phosphorylation. A structure-activity relationship (SAR) study was undertaken to choose a derivative that would be both poisonous to rodents but still readily consumed by them. This approach led to the discovery of bromethalin,... 

Table II. Uncoupling of Oxidative Phosphorylation by Phenols at pH 7.5 and Physicochemical Constants Used ...

Toxicology. 2,4-Dichlorophenol (2,4-DCP) is an uncoupler of oxidative phosphorylation toxic manifestations include central nervous system depression followed by increased respiration, hyperthermia, increased blood pressure, progressive weakness, and cyanosis. 

The oral LDso in rats was 2830mg/kg. Typical effects associated with acute lethal oral doses have included restlessness and increased respiratory rate, which appear quickly, followed shortly by tremors, convulsions, dyspnea, coma, and death. The primary toxic mechanism is the uncoupling of oxidative phosphorylation. ... 

Moreno-Sanchez, R. et al. (1999) Inhibition and uncoupling of oxidative phosphorylation by nonsteroidal antiinflammatory drugs study in mitochondria, submitochondrial particles, cells, and whole heart. Biochemical Pharmacology, 57 (7), 743-752. 

Metabolic effects Salicylates cause uncoupling of oxidative phosphorylation which leads to conversion of energy into heat and may thus produce hyperpyrexia and increased protein catabolism. Larger dose produces hyperglycemia and glycosuria in normal individual while in diabetic patient it produces hypoglycemia which may be due to an enhanced peripheral utilization of glucose and inhibition of... 

Metabolic acidosis follows, and an increased anion gap results from accumulation of lactate as well as excretion of bicarbonate by the kidney to compensate for respiratory alkalosis. Arterial blood gas testing often reveals this mixed respiratory alkalosis and metabolic acidosis. Body temperature may be elevated owing to uncoupling of oxidative phosphorylation. Severe hyperthermia may occur in serious cases. Vomiting and hyperpnea as well as hyperthermia contribute to fluid loss and dehydration. With very severe poisoning, profound metabolic acidosis, seizures, coma. 

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