Uncouplers toxicity

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. 

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). 

Dinitrophenol is a member of the aromatic family of pesticides, many of which exhibit insecticide and fungicide activity. DNP is considered to be highly toxic to humans, with a lethal oral dose of 14 to 43mg/kg. Environmental exposure to DNP occurs primarily from pesticide runoff to water. DNP is used as a pesticide, wood preservative, and in the manufacture of dyes. DNP is an uncoupler, or has the ability to separate the flow of electrons and the pumping of ions for ATP synthesis. This means that the energy from electron transfer cannot be used for ATP synthesis [75,77]. The mechanism of action of DNP is believed to inhibit the formation of ATP by uncoupling oxidative phosphorylation. 

The toxicity of commercial or technical grades of PCP significantly exceeds that of analytical or purified PCP. Some of this added toxicity is attributed to impurities such as dioxins, dibenzo-furans, chlorophenols, and hexachlorobenzene. Pentachlorophenol is rapidly accumulated and rapidly excreted, and has little tendency to persist in living organisms. It acts by uncoupling oxidative... 

Uncoupling is a specific toxic effect that takes place in energy-transducing membranes (photosynthetically active membranes, inner mitochondrial... 

Polynitroaromatic compounds are used as explosives. They are toxic and might cause liver damage, methemoglobinemia and uncoupling of the oxidative phosphorylation process. Trace analyses of polynitroaromatic residues in groundwater, surface water, rainwater... 

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. 

Answer C. The toxic agent (example, 2,4-dinitrophenol) would uncouple oxidative phosphorylation, leading to a fall in ATP levels, increased respiration, and increased substrate utilization. 

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,... 

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. ... 

For many of the drugs associated with hepatotoxicity, there are examples of structurally related drugs which are latent to bioactivation and toxicity because of the absence of the toxicophore or the existence of alternate metabolic pathways. For example, the hepatotoxicity associated with the use of the anti-Parkinson s agent tolcapone does not occur with the structurally related drug entacapone, despite administration at doses similar to tolcapone (200-1000 mg QD). This disparity may be explained in part by the observation that entacapone does not succumb to the bioactivation reactions of tolcapone in humans (Scheme 15.3) [35]. It is also noteworthy that tolcapone but not entacapone is a potent uncoupler of oxidative... 

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