Respiration, cellular inhibition

Fluorocitrate is therefore a pseudosubstrate. As well as inhibiting cellular respiration, inhibition of the TCA cycle will also reduce the supply of 2-oxoglutarate. This may decrease the removal of ammonia via formation of glutamic acid and glutamine, and this might account for the convulsions seen in some species after exposure to fluoroacetate. The toxicity is manifested as a malfunction of the CNS and heart, giving rise to nausea, apprehension, convulsions, and defects of cardiac rhythm, leading to ventricular fibrillation. Fluoroacetate and fluorocitrate do not appear to inhibit other enzymes involved in intermediary metabolism, and the di- and trifluoroacetic acids are not similarly incorporated and therefore do not produce the same toxic effects. 

Cellular respiration inhibition Berberine Isoquinoline alkaloid 304... 

HCN is among the most rapidly acting of all known poisons. Absorption occurs by all routes the mechanism of action is inhibition of cellular respiration. The respiratory, central nervous, and cardiovascular systems are the primary targets of an acute exposure. Information on human exposures was limited to exposures to high concentrations for short time intervals, poorly documented accidental exposures, and chronic occupational exposures. 

In the rabbit eye, a drop of the liquid caused superficial injury. The liquid on the belly of a rabbit caused a faint erythema of short duration. The toxic effects of acetonitrile are attributed to the metabolic release of cyanide via hepatic metabolism cyanide in turn acts by inhibiting cytochrome oxidase and thus impairs cellular respiration. Evidence of the cyanide effect is supported by the reported effectiveness of specific cyanide antidotes in acetonitrile poisonings. ... 

At the cellular level, rotenone inhibits cellular respiration by blocking electron transport between flavoprotein and ubiquinone. It also inhibits spindle microtubule assembly. ... 

Several mechanisms have been postulated to account for thallium s toxicity, including ligand formation with sulfhydryl groups of enzymes and transport proteins, inhibition of cellular respiration, interaction with riboflavin and riboflavin-based cofactors, alteration of the activity of K -dependent proteins, and disruption of intracellular calcium homeostasis. ... 

Alkaloids such as berberine are known to be anti-microbial. They inhibit estarases as well as DNA and RNA polymerases. Moreover, berberine inhibits cellular respiration and acts in DNA intercalation. As a strong anti-microbial agent, berberine may be used in the treatment of AIDS, as it inhibits HIV-I reverse transcriptase. Berberine also has uses in the treatment of infections, specifically eye infections and hepatitis. 

NO also has cytotoxic effects when synthesized in large quantities, eg, by activated macrophages. For example, NO inhibits metalloproteins involved in cellular respiration, such as the citric acid cycle enzyme aconitase and the electron transport chain protein cytochrome oxidase. Inhibition of the heme-containing cytochrome P450 enzymes by NO is a major pathogenic mechanism in inflammatory liver disease. 

This type of effect can occur in all tissues and is caused by a metabolic inhibitor such as azide or cyanide, which inhibits the electron transport chain. Inhibition of one or more of the enzymes of the tricarboxylic acid cycle such as that caused by fluoroacetate (Fig. 6.7) also results in inhibition of cellular respiration (for more details of cyanide and fluoroacetate see chap. 7). 

Excessive muscular blockade may be caused by compounds such as the cholinesterase inhibitors. Such inhibitors, exemplified by the organophosphate insecticides such as malathion (chap. 5, Fig. 12) (see also chap. 7) and nerve gases (e.g., isopropylmethylphosphonofluor-idate), cause death by blockade of respiratory muscles as a result of excess acetylcholine accumulation. This is due to inhibition of the enzymes normally responsible for the inactivation of the acetylcholine (see chap. 7). Respiratory failure may also result from the inhibition of cellular respiration by cyanide, for example, or central effects caused by drugs such as dextropropoxyphene. 

Physiological, pharmacological, and biochemical responses do not usually lead to a tissue lesion, although there may be organ failure as a result. They may result from interactions of chemicals with receptors or specific enzymes leading to anoxia, inhibition of cellular respiration, respiratory failure, changes in pH, temperature, blood pressure or electrolyte balance, for example. 

Berberine inhibits oxidative decarboxylation of yeast pyruvic acid (310) the same dose has, however, no effect upon aerobic glycolysis, Warburg s respiratory enzymes, indophenol oxidase, etc. Berberine and tetrahydroberberine have an inhibitory effect on oxidation of (+ )-alanine in rat kidney homogenates (498). Berberine and palmatine show a specific inhibitory effect upon cholinesterase in rabbit spleen and on pseudocholinesterase in horse serum (499). Berberine inhibits cellular respiration in ascitic tumors and even in tissue cultures (500-502). The specific toxic effect of berberine on the respiration of cells of ascitic tumors in mice was described (310). The glycolysis was not found to be affected, but the uptake of oxygen was smaller. Fluorescence was used in order to demonstrate berberine in cellular granules. Hirsch (503) assumed that respiration is inhibited by the effect of berberine on the yellow respiratory enzymes. Since the tumorous tissue contains a smaller number of yellow respiratory enzymes than normal tissue it is more readily affected by berberine. Subcutaneous injections of berberine, palmatine, or tetrahydropalmatine significantly reduce the content of ascorbic acid in the suprarenals, which is not affected by hypophysectomy (504). 

Free silver ions are the active components of antimicrobial silvers, and it has been shown that as little as one part per million of elemental silver in solution is an effective antimicrobial. Materials such as polymers, charcoal, and hydrocolloids when formulated with silver not only aid wound management and healing but also regulate its release into the wound environment and surrounding tissues. Silver ions kill micro-organisms by inhibiting cellular respiration and cellular function. " It is known that their mode of action is exerted by binding cysteine residues on the cell walls of yeasts such as C. albicans thereby... 

Acrylonitrile owes some of its toxicity to cyanide generation, which inhibits cellular respiration. Preinduction of microsomal mixed function oxidase (MFO) with Arochlor 1254 greatly enhanced the toxicity of acrylonitrile and caused a threefold increase in cyanide levels in rats. Therefore, metabolic activation appears to be necessary in the toxicity of acrylonitrile. The direct reaction of acrylonitrile with the SH groups of proteins and its epoxide metabolite are also expected to be responsible for its effects. 

Adiponitrile s mechanism of toxicity is similar to cyanide because it can potentially liberate cyanide in the body spontaneously. It forms a stable complex with ferric iron in the cytochrome oxidase enzymes, thereby inhibiting cellular respiration. Cyanide affects primarily the central nervous system (CNS), producing early stimulation followed by depression. It initially stimulates the peripheral chemoreceptors (causing increased respiration) and the carotid bodies (thereby slowing the heart). Early CNS, respiratory, and myocardial depression result in decreased oxygenation of the blood and decreased cardiac output. These effects produce both stagnation and hypoxemic hypoxia in addition to cytotoxic hypoxia from inhibition of mitochondrial cytochrome oxidase. 

Cobalt most often depresses the activity of enzyme including catalase, amino levulinic acid synthetase, and P-450, enzymes involved in cellular respiration. The Krebs citric acid cycle can be blocked by cobalt resulting in the inhibition of cellular energy production. Cobalt can replace zinc in a number of zinc-required enzymes like alcohol dehydrogenase. Cobalt can also enhance the kinetics of some enzymes such as heme oxidase in the liver. Cobalt interferes with and depresses iodine metabolism resulting in reduced thyroid activity. Reduced thyroid activity can lead to goiter. 

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