Poisons, oxidative phosphorylation

Sulflutamid or A/-ethylpetfluotoctanesulfonamide [4151 -50-2] CgF yS02NHC2H, is a slow-acting stomach poison used in baits for the control of ants and cockroaches. It acts as an uncoupler of oxidative phosphorylation. 

Much information about the respiratory chain has been obtained by the use of inhibitors, and, conversely, this has provided knowledge about the mechanism of action of several poisons (Figure 12-7). They may be classified as inhibitors of the respiratory chain, inhibitors of oxidative phosphorylation, and uncouplers of oxidative phosphorylation. 

Inhibitors may act reversibly or irreversibly to limit the activity of the enzyme. Irreversible inhibitors are enzyme poisons and indeed many of them are poisonous in the common sense of the word cyanide for example, is an irreversible inhibitor of one of the cytochromes in oxidative phosphorylation. 

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,... 

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. 

The mechanism of toxicity of ethylene glycol involves metabolism, but unlike previous examples, this does not involve metabolic activation to a reactive metabolite. Thus, ethylene glycol is metabolized by several oxidation steps eventually to yield oxalic acid (Fig. 7.84). The first step is catalyzed by the enzyme alcohol dehydrogenase, and herein lies the key to treatment of poisoning. The result of each of the metabolic steps is the production of NADH. The imbalance in the level of this in the body is adjusted by oxidation to NAD coupled to the production of lactate. There is thus an increase in the level of lactate, and lactic acidosis may result. Also, the intermediate metabolites of ethylene glycol have metabolic effects such as the inhibition of oxidative phosphorylation, glucose metabolism, Krebs cycle, protein synthesis, RNA synthesis, and DNA replication. 

A number of substances inhibit oxidative phosphorylation at specific locations. These may be divided into agents that affect electron transport, those that affect complex V, and those that collapse proton gradients (proton ionophores). Such substances have been used as research tools to unravel the complexities of these pathways, as poisons, and as antibiotics. Inhibition of electron transport inhibits phosphorylation, the extent of which depends on the location of the inhibition site. Thus, if complex I is inactivated, electron transport can still take place using FADH2 as an electron donor. The donor P/O ratio is then 2. 

The mechanism of action of DNOC depends on its ability to uncouple oxidative phosphorylation and consequently cause elevated metabolic rates and hyperthermia. There is no antidote to arrest or reverse the metabolic disturbances in humans exposed to DNOC. However, 4-methyl-2-thiouracil has been given to DNOC-poisoned animals to reduce high metabolic rates and other toxic effects of... 

R3MX are the most poisonous in the R4 MX (M = Sn, Pb) series this is also observed for the isostructural compounds of silicon . The toxic action of compounds of tin and lead is similar. Derivatives of R3MX inhibit oxidative phosphorylation, whereas R2MX2 binds thiol enzymes groups. Fungicidal activity of trialkylstannane R3MX derivatives is maximal when the number of carbon atoms is 9 in all three R substituents. On the whole, the toxicity of organic compounds of tin and lead decreases as the bulk of the substituents about the central metal atom increases. 

Cyanide poisoning is marked by metabolic acidosis and a large anion gap. The latter is a consequence of the blocked oxidative phosphorylation and the increased rate of glycolysis. Maduh et al (1990) showed that cyanide also affects and thus the pH of the tissues. In turn, the Ca transport process is disrupted, leading to a rise in cystolic [Ca ]. Acidification depolarizes the cell membrane and changes the potassium conductance. 

D-10) Antimycin A, a fungal antibiotic, blocks oxidative phosphorylation at the step between cytochromes b and C. Rotenone, a toxic plant derivative used as a fish poison, and amytal, a baibituate sedative, both interrupt electron transport in the step between NADH and FMN. 

Arsenic, in its arsenate (AsO ") form prevents the se quential transformation of glyceraldehyde 3-P to 3-P glycerate (D-5). Arsenate resembles phosphate and can substitute for it in oxidative phosphorylation, and also attach to glyceraldehyde 3-P, in place of phosphate. The resultant unstable arsenate compound does change to the normal end result, 3-P-glycerate, but without the normal production of an ATP. This is poisonous. 

Local anesthetics have a wide range of effects. They inhibit sodium, potassium, and calcium ion channels, alpha-adrenoceptors, and phosphatidylinositol signalling. They also cause dysrhythmias when injected directly into the brain. Local anesthetics are also mitochondrial poisons and impair oxidative phosphorylation. 

Phosphorus is an oxidizing agent that, when exposed to air, may burn spontaneously. Thus, direct contact may result in both thermal and chemical burns. Second- and third-degree burns can be seen at the point of contact. When absorbed, phosphorus will act as a cellular poison by uncoupling oxidative phosphorylation. 

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