Metabolic uncoupling

Hypothermia—Indirect cryodestruction Metabolic uncoupling Energy deprivation Ionic imbalance Disruption of acid-base balance Waste accumulation Membrane phase transitions Cytoskeletal disassembly Frozen State—Direct cryodestruction Water solidification Hyperosmolality Cell-volume disruption Protein denaturation Tissue shearing Intracellular-ice propagation Membrane disruption Microvascular Thawed State Direct effects... 

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. 

Salicylate is an intermediate in the metabolism of PAHs including naphthalene and phen-anthrene, and its degradation involves oxidation to catechol. The hydroxylase (monooxygenase) has been extensively studied (references in White-Stevens and Kamin 1972) and in the presence of an analog that does not serve as a substrate, NADH is oxidized with the production of H2O2 (White-Stevens and Kamin 1972). This uncoupling is characteristic of flavoenzymes and is exemplified also by the chlorophenol hydroxylase from an Azotobacter sp. that is noted later. 

There are numerous in vitro and in vivo studies, in which the damaging free radical-mediated effects of iron have been demonstrated. Many such examples are cited in the following chapters. However, recent studies [170,171] showed that not only iron excess but also iron deficiency may induce free radical-mediated damage. It has been shown that iron deficiency causes the uncoupling of mitochondria that can be the origin of an increase in mitochondria superoxide release. Furthermore, a decrease in iron apparently results in the reduction of the activity of iron-containing enzymes. Thus, any disturbance in iron metabolism may lead to the initiation of free radical overproduction. 

Fox, P. T. and Raichle, M. E. Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc. Natl Acad. Sci. U.S.A. 83 1140-1144,1986. 

Paul John McCarron, I thought you had some evidence from the inhibition of oxidative metabolism that this messes up the uncoupling ... 

The first defect, described in 1962 is, in fact, one of the rarest (Luft s syndrome). It arises from the uncoupling of mitochondria. The resting metabolic rate is markedly raised, there is profuse sweating, fever and generalised muscle weakness. The mitochondria of these patients have an increased permeability, not so much to protons, as in brown adipose tissue mitochondria, but to cations, such as Ca, the entry of which similarly dissipates the proton motive force. 

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... 

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. 

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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