Phosphorylation, adenosine oxidation, uncoupling

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. 

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 many years, niclosamide (Niclocide) was widely used to treat infestations of cestodes. Niclosamide is a chlorinated salicylamide that inhibits the production of energy derived from anaerobic metabolism. It may also have adenosine triphosphatase (ATPase) stimulating properties. Inhibition of anaerobic incorporation of inorganic phosphate into ATP is detrimental to the parasite. Niclosamide can uncouple oxidative phosphorylation in mammalian mitochondria, but this action requires dosages that are higher than those commonly used in treating worm infections. 

Those who are familiar with, or have read the section on DNP are aware of the term "oxidative phosphorylation". This is a process by which cells/mitochondria convert ADP (Adenosine Diphosphate) into ATP (Adenosine Triphosphate). Basically this means adding another phosphate molecule to ADP so that it can be converted back into the body s energy /ATP. But the term keeps kids flunking biology anyway. DNP makes cells waste calories and burn fat by "uncoupling" the oxidative phosphorylation process and making it less efficient, even when at rest. 

Phosphorylation of ADP to ATP by mitochondria is driven by an electrochemical proton gradient established across the inner mitochondrial membrane as a consequence of vectoral transport of protons from NADH and succinate during oxidation by the respiratory chain (see Chapter 17). Hence, lipophilic weak acids or bases (such as 2,4-dinitrophenol) that can shuttle protons across membranes will dissipate the proton gradient and uncouple oxidation from ADP phosphorylation. Intrami-tochondrial ADP can be rate-limiting as demonstrated by inhibition of the mitochondrial adenosine nucleotide carrier by atractyloside. Inhibition of ATP synthesis... 

There is little information on the effect of tin on enzymes. Organic tin compounds can inhibit the hydrolysis of adenosine triphosphate, resulting in uncoupling of oxidative phosphorylation. 

DNP is an uncoupler of oxidative phosphorylation. In humans or animals exposed to 2,4-DNP, the energy produced from the Krebs cycle is not stored in adenosine triphosphate (ATP), but is released as heat. This short-circuiting of metabolism results in the characteristic clinical signs of increased basal metabolic rate, oxygen consumption, perspiration, and body temperature. Elevated environmental temperatures may compromise the body s ability to dissipate the heat. 

A similar inconsistency exists concerning oxidative phosphorylation in AD. Although activities of enzymes of the mitochondrial electron transfer chain are reported to be normal in AD brain, partial uncoupling of oxidative phosphorylation (electron transfer and phosphorylation of adenosine diphosphate are normally functionally linked) (Sims et al., 1987) and overexpression of cytochrome oxidase subunit-3 gene in cerebral temporal cortices (Alberts et al., 1992) have been reported. In addition, substantial decreases of complex IV activity were detected in platelets from five patients with AD (Parker et al., 1990). 

Because of the role of mitochondria in cellular respiration and energy production, efforts to elucidate the mechanism of thyroid hormone action in metabolism and calorigenesis have focused on mitochondrial studies. Thyroid hormones in vitro are known to uncouple oxidative phosphorylation in isolated mitochondria, but these effects occur at unphysiological doses of T4. In physiological concentrations, T4 increases adenosine triphosphate (ATP) formation and the number and inner membrane surface area of mitochondria (21), but T4 does not reduce the efficiency of oxidative phosphorylation. Furthermore, 2,4-dinitrophenol, a classic uncoupler of oxidative phosphorylation, can neither relieve hypothyroidism nor duplicate other physiological effects of thyroid hormones. 

A. Pentachlorophenol and dinitrophenols uncouple oxidative phosphorylation in the mitochondria. Substrates are metabolized but the energy produced is dissipated as heat instead of producing adenosine triphosphate (ATP). The basal metabolic rate increases, placing increased demands on the cardiorespiratory system. Excess lactic add results from anaerobic glycolysis. 

An ex vivo study with rat hepatocytes found a strong correlation between the cytotoxicity of a flavonoid and its ability to induce an early collapse of the mitochondrial transmembrane potential [6]. In contrast, nontoxic flavonoids had no effect on the transmembrane potential. As discussed previously, the ability of flavonoids and isoflavones to inhibit mitochondrial respiration and adenosine triphosphate (ATP) synthesis or uncouple oxidative phosphorylation represents a potential mechanism whereby they can trigger dissipation of the transmembrane potential and thus cytochrome c-dependent apoptosis. Thus, it is interesting to note that epicatechin, which had little or no proapoptotic effect in cancer cells [64] and exerted antiapoptotic effects in primary culture models [7,8,59], had essentially no inhibitory effect against complex I, II, or HI activity and FoFi-ATPase activity [24,25]. However, the preceding discussion has also indicated that the pro- or antiapoptotic effects of flavonoids may be explained by more specific mechanisms, potentially independently of their antioxidant capacity. These include effects on protein kinase cascades and gene expression, including MARK and the Bcl-2 family of proteins. 

UiKOupliitg of oxidative phosphorylation. The release of energy in the electron transport chain becomes uncoupled from the formation of energy by the phosplxirylation of adenosine diphosphate (ADP) to ATP. 

Uncouples oxidative phosphorylation in the CNS, leading to loss of energy metabolism and decreasing the activity of the sodium pump, causing cerebral edema Inhibits adenosine receptors and phosphodiesterase, increasing cAMP production enhances catecholamine release and effects... 

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