Histotoxic hypoxia

Cytochrome c oxidase (an enzyme in the mitochondrial respiratory chain) is sensitive to cyanide action (Way 1984). Due to its inhibition, oxygen cannot be utilized, histotoxic hypoxia develops, and this can lead to deaths of humans and animals (see Section 2.3.3). 

A). Cyanide ions (CN ) enter the organism in the form of hydrocyanic acid (HCN) the latter can be inhaled, released from cyanide salts in the acidic stomach juice, or enzymatically liberated from bitter almonds in the gastrointestinal tract The lethal dose of HCN can be as low as 50 mg. CN binds with high affinity to trivalent iron and thereby arrests utilization of oxygen via mitochondrial cytochrome oxidases of the respiratory chain An internal asphyxiation (histotoxic hypoxia) ensues while erythrocytes remain charged with O2 (venous blood colored bright red). 

Formic acid is an inhibitor of cytochrome oxidase at the terminal end of the respiratory chain in mitochondria and causes histotoxic hypoxia at the cellular level. Therefore, persons with cardiovascular disease may be considered at special risk to the affects of formic acid. ... 

The toxic effect is known as histotoxic hypoxia. Cyanide also directly stimulates chemoreceptors, causing hyperpnea. Lack of ATP will affect all cells, but heart muscle and brain are particularly susceptible. Therefore, cardiac arrythmias and other changes often occur, resulting in circulatory failure and delayed tissue ischemic anoxia. Death is usually due to respiratory arrest resulting from damage to the CNS, as the nerve cells of the respiratory control center are particularly sensitive to hypoxia. The susceptibility of the brain to pathological damage may reflect the lower concentration of cytochrome oxidase in white matter. 

The other major toxic effect of methanol is the ocular toxicity. Although formaldehyde might be formed locally in the retina, this seems unlikely, whereas formate is known to cause experimental ocular toxicity. The mechanism suggested involves inhibition by formate of cytochrome oxidase in the optic nerve. As the optic nerve cells have few mitochondria, they are very susceptible to this "histotoxic hypoxia,"... 

Liesivuori and Savolainen (1991) studied the biochemical mechanisms of toxicity of methanol and formic acid. Formic acid is an inhibitor of the enzyme mitochondrial cytochrome oxidase causing histotoxic hypoxia. It is, however, a weaker inhibitor than cyanide and hydrosulfide anions. The effects of its acidosis are dilation of cerebral vessels, facilitation of the entry of calcium ions into cells, loss of lysosomal latency, and deranged production of ATP, the latter affecting calcium reabsorption in the kidney tubules. Also, urinary acidification from formic acid and its excretion may cause continuous recycling of the acid by the tubular cell Cl-/formate exchanger. Such sequence of events probably causes an accumulation of formate in urine. Other than methanol, methyl ethers, esters, and amides also metabolize forming formic acid. 

Chemical asphyxiates are toxic agents which enter into reactions to cause histotoxic hypoxia. These chemicals prevent the red blood cells from carrying oxygen. Some more familiar chemical asphyxiates are carbon monoxide, nitrites, hydrogen sulhde, and aniline. 

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