Inhibitors of Cellular Respiration

Table 9. 7-Substituted 4-hydroxyquinoline-3-carboxylic acids (5) as inhibitors of cellular respiration [293]...

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. 

Addition of NO donors, ImM S-nitroso-N-acetyl-DL-penicillamine or 1 mM diethylenetri-amine-NO adduct (NOC-18), to PC12 cells resulted in a steady-state level of 1-3 (xM NO, rapid and almost complete inhibition of cellular respiration (within 1 min), and a rapid decrease in mitochondrial membrane potential within the cells (Bal-Price and Brown 2000). A 24-h incubation of PC12 cells with NO donors or specific inhibitors of mitochondrial respiration (myxothiazol, rotenone, or azide), in the absence of glucose, caused total ATP depletion and resulted in 80-100% necrosis. The presence of glucose almost completely prevented the decrease in ATP level and the increase in necrosis induced by NO donors or mitochondrial inhibitors. 

The active site of mbisco, the key enzyme involved in photosynthesis, can accept either CO2 or O2. Thus, O2 is a competitive inhibitor of photosynthesis. This process is known as photo-respiration, and involves addition of O2 to ribulose-biphosphate. Products of this reaction enter a metabolic pathway that eventually produces CO2. Unlike cellular respiration, photo-respiration generates no ATP, but it does consume O2. In some plants, as much as 50% of the carbon fixed by the Calvin cycle is respired through photorespiration. Photorespiration is enhanced in hot, dry environments when plant cells close stomata to slow water loss, CO2 is depleted and O2 accumulates. Photorespiration does not occur in prokaryotes, because of the much lower relative concentration of O2 versus CO2 in water compared with air. 

The exact mechanism(s) responsible for fluoride s nephrotoxicity remain to be defined. The fluoride ion interferes with normal cell function on several levels. Fluoride is an inhibitor of several cellular enzyme systems and dirninishes tissue respiration and anaerobic glycolysis [89]. In the kidney, fluoride interferes with transport of sodium in the proximal convoluted tubule. It also inhibits adenylate cyclase in the collecting system and dirninishes the action of antidiuretic hormone. Experimental evidence in rats indicates that the chloride dependent pump, in the thick ascending part of Henle s loop, also is inhibited [90]. In human collecting duct cell cultures, exposure to fluoride ions inhib-... 

MPP+ is a potent inhibitor of oxidation of the NAD+-linked substrates pyruvate/malate and glu-tamate/malate in isolated rat liver and brain mitochondria, while leaving the oxidation of succinate unaffected (Nicklas et al., 1985). The locus of inhibition of the mitochondrial respiration is assumed to be between the highest potential Fe-S cluster in NADH dehydrogenase and the coenzyme Q located probably at the rotenone-binding site (Ramsay et al., 1991). As a consequence of inhibition of respiration, cellular energy supplies in the form of ATP would rapidly be consumed, followed by depolarization of membranes, probable Ca influx and overstimulation of Ca +-dependent lysosomal enzymes. 

Chromophores which are non-toxic at low concentrations may become potent inhibitors if they are concentrated in specific compartments. Cyanine dyes severely inhibit respiration at site 1 of the mitochondrial respiratory chain, providing that the inner mitochondrial membrane potential is substantial (inside negative) (18). In living cells, the irmer mitochondrial membrane potential is about 180 mV and the plasma membrane potential is about 60 mV (both inside negative), and extracellular csranine at 10" m is at electrochemical eqrrilibrium with mitochondrial cyanine when the latter reaches 10 m. Very low concentrations of cyanines may thus adversely affect cellular respiration and energy dependent processes (18). 

Hydrazoic acid, HN3, is a colorless, explosive liquid. It is a weak acid whose salts are called azides. Heavy-metal azides, like the acid, are unstable and are employed as detonators for explosives. Sodium azide, NaN3, is used by biochemists to study cellular respiration. The linear, symmetric azide ion, [N"=N=N] , serves as an inhibitor of the key electron transfer step. 

Hydrogen cyanide is widely used in industry in the manufacture of plastics and nitrites and may also be produced by burning polyurethane foam. It is also found in very small quantities in the kernels of some fruits. It may be ingested or inhaled accidentally or deliberately. It may also form explosive mixtures. All cyanides are reversible cytochrome oxidase inhibitors, which prevent cellular respiration. 

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