Answer to Question B-09
As described in a former post, the inhibitors of the Electron Transport Chain are substances that bind to some of the components of the ETC blocking its ability to change in a reversible form from an oxidized state to a reduced state.
This inhibition results in the accumulation of reduced forms before the inhibitor point, and oxidized forms of the components of the ETC downstream (ahead) the inhibition point.
Since energy is not released, the synthesis of ATP also stops. The most important known inhibitors of the ETC are Amytal, Rotenone, Antimycin A, CO, Sodium Azide, and Cyanides.
Amytal, a barbiturate, and Rotenone, a plant product used as insecticide and pesticide, block the ETC between NADH dehydrogenase (Complex I) and CoQ.
Consequently, they prevent the utilization of NADH as a substrate. On the contrary, electron flow resulting from the oxidation of Complex II is not affected, because these electrons enter through QH2, beyond the block.
The effect of Amytal has been observed in vitro, since the intoxication with amytal and other barbiturates in vivo affect mainly the CNS by acting on GABA-sensitive ion channels, an effect not related to the action of Amytal on Complex I.
Rotenone intoxications are very rare. In facts, some human tribes used to catch fishes by spreading plant extracts containing rotenone in the water, and this substance was easily absorbed by the fishes through the gills. These fishes were eaten later without notable side effects in humans, since rotenone is absorbed very difficult by the gastrointestinal tract. Usually, when taken in a concentrated form, irritating action in mucoses causes vomits.
It is interesting to note that Rotenone and MPTP (a neurotoxin), when administered in vein, cause at the same time interference with the functioning of Complex I and a Parkinson-like disease. These substances affect primary neurons in substancia nigra; apparently the sequence is: impairment of Complex I, impairment of mitochondria metabolism, accumulation of free radicals, cell death, release of toxic compounds and destruction of other cells.
Antimycin A is an antibiotic produced by Streptomyces griseous that has been used as a piscicide for the control of some fish species. Antymicine A interferes with electron flow from cytochrome bH in Complex III (Q-cytochrome c oxidoreductase). In the presence of this substance, cytochrome bH can be reduced but not oxidized, consequently, in the presence of antimycin A cytochrome c remains oxidized, as do the cytochromes a and a3 that are ahead.
Carbon monoxide (CO) is responsible for more than 50 % of death by poisoning worldwide. It is colorless and odorless; high levels can result from incomplete combustion of fuels: engine and furnace exhausts are important sources. Tobacco smoking increases CarboxyHb levels.
Carbon monoxide intoxication causes impaired oxygen delivery and utilization at the cellular level. The affinity of Hb for CO is almost 300 times higher than for Oxygen. An environment in which there is 100 ppm of CO is enough to form 16 % carboxyhemoglobin. The situation is worsen since the binding of CO to one of the Hem groups of Hemoglobin increases the affinity of the other three Hem groups for Oxygen, so the delivery of Oxygen to tissues is very affected. The brain and the heart, that has a high Oxygen consumption, are the most affected. Myoglobin has even a greater affinity for CO than Hemoglobin. As a consequence of the binding of CO to these molecules, the heart functioning is very impaired and the patient presents sever hypotension. As described above, this intoxication is an important cause of death worldwide.
The affinity of respiratory chain components for CO is lower than for Oxygen,
but since the clinical status does not correlate very well with the carboxyhemoglobin levels, it is considered that the inhibition of Cytochrome Oxidase by CO also plays a role in CO intoxication. CO binds to the reduced form of iron in Hem groups (Fe++) in cytochrome Oxidase
On the contrary, in cyanide intoxication the inhibition of the respiratory chain has a primary role. Intoxication by cyanide can be seen relatively frequent in patients with smoke inhalation from residential or industrial fires. Also in persons related professionally with cyanide or derivatives in certain industries. Intentional poisoning can be seen in suicidal persons with access to cyanide compounds. Cyanide affects practically all metalloenzymes, but its principal toxicity derives from the binding to the Fe+++ in the Hem groups in cytochrome Oxidase, inhibiting the functioning of the Electron Transport Chain. As a consequence, redox reactions in the respiratory chain will stop, energy will not be released, proton pumps will not function, so they will not return through Complex V, and the production of ATP will cease (Related question here).
Azides have an action on the respiratory chain very similar to cyanide, inhibiting the Hem groups of cytochromes in Cytochrome Oxidase (Complex IV). Azides are used as propellants in airbags, in detonant (explosive) industry and as preservative of sera an reagents. Some cases of azide intoxication in humans have been reported.
You can find more information about these inhibitors of the Electron Transport Chain in these links:
Antimycin A: toxicity, ecological toxicity and regulatory information
Risk assessment for Piscicidal Formulations of Antimycin
Leybell, I: Toxicity: Cyanide
Cyanide poisoning
Azide Toxicity
Sodium Azide Toxicity effects
Shochat, G.N.: Toxicity, Carbon Monoxide
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