Cytochrome oxidase, mechanism action

Nature has had a long time to perfect her inorganic chemistry, and understanding the mechanisms of enzymatic action can suggest ways for the inorganic chemist to develop corresponding in vitro catalysts. We shall show how knowledge of cytochrome oxidase and cytochrome P-450 has led to such possibilities. 

HCN is a systemic poison toxicity is due to inhibition of cytochrome oxidase, which prevents cellular utilization of oxygen. Inhibition of the terminal step of electron transport in cells of the brain results in loss of consciousness, respiratory arrest, and ultimately, death. Stimulation of the chemoreceptors of the carotid and aortic bodies produces a brief period of hyperpnea cardiac irregularities may also occur. The biochemical mechanisms of cyanide action are the same for all mammalian species. HCN is metabolized by the enzyme rhodanese which catalyzes the transfer of sulfur from thiosulfate to cyanide to yield the relatively nontoxic thiocyanate. 

Its action has been postulated to be intraneuronal on the oxidation cycle at a phase above the cytochrome b level of the cytochrome oxidase system though its precise mechanism has not been elucidated. It is primarily a neurotoxin with a chemical structure that allows for easy penetration of the blood-brain barrier. 

The mechanism of action of the phenothiazines is still not definitely known. They tend to block important effector substances such as acetylcholine, epinephrine, and histamine. The phenothiazines produce uncoupling of phosphorylation from oxidation. They appear to act at all steps along the electron transport chain. Cytochrome oxidase, succinoxidase, and adenosine triphosphatase are inhibited. Some data indicate that the phenothiazines may decrease the permeability of storage granules for brain amines. 

I. Mechanism of toxicity. Hydrogen sulfide causes cellular asphyxia by inhibition of the cytochrome oxidase system, similar to the action of cyanide. Because it is rapidly absorbed by inhalation, symptoms occur nearly immediately after exposure, leading to rapid unconsciousness or knockdown. Hydrogen sulfide is also a mucous membrane irritant. 

L The answer is d. (Hardman, p 906.) Cimetidine slows the metabolism of Ca channel blockers, which are substrates for hepatic mixed-function oxidases. Inhibition of cytochrome P450 activity is peculiar to cimetidine and is not a mechanism of action of other histamine 2 (Hz) blockers. 

If one were required to name the most important enzyme in the body, one might name cytochrome c oxidase, because of its vital initerfacing with oxidative metabolism and O . At this point, electrons derived from components of the diet meet the oxygen absorbed by the lungs. Cytochrome c oxidase is a multisubunit protein containing about a dozen proteins. These include two cytochromes (e and aj) and two copper proteins. A simplified mechanism of action for cytochrome c oxidase is outlined in four steps in Figure iO 26... 

Thiram and other dithiocarbamates are metabolic poisons. The acute effects of thiram are very similar to that of carbon disulfide, supporting the notion that the common metabolite of this compound is responsible for its toxic effects. The exact mechanism of toxicity is still unclear, however it has been postulated that the intracellular action of thiram involves metabolites of carbon disulfide, causing microsome injury and cytochrome P450 disruption, leading to increased heme-oxygenase activity. The intracellular mechanism of toxicity of thiram may include inhibition of monoamine oxidase, altered vitamin Bg and tryptophan metabolism, and cellular deprivation of zinc and copper. It induces accumulation of acetaldehyde in the bloodstream following ethanol or paraldehyde treatment. Thiram inhibits the in vitro conversion of dopamine to noradrenalin in cardiac and adrenal medulla cell preparations. It depresses some hepatic microsomal demethylation reactions, microsomal cytochrome P450 content and the synthesis of phospholipids. Thiram has also been shown to have moderate inhibitory action on decarboxylases and, in fish, on muscle acetylcholinesterases. 

---