Cytochrome c oxidase inhibition

Cytochrome C oxidase inhibition. Smoke extract, in the mouse brain mitochondria culture in the presence or absence of vitamin C for 60 minutes, inhibited mitochon-... 

The early development of tachypnoea, usually accompanied by hyperpnoea, and resulting in an increased tidal volume, is frequently ascribed to stimulation of the carotid and aortic chemore-ceptors as a result of local accumulation of acid metabolites following cytochrome c oxidase inhibition. However, the general blood acid-base balance changes, notably lactate acidosis, may also be an important factor in breathing changes. 

Mechanism of toxicologic damage. Phosphide salts cause respiratory and gastrointestinal irritation and inhibit cjdochrome C mddas but the relationship bebveen cytochrome C oxidase inhibition and clinical effects is unclear. 

Smith L, Kruszyna H, Smith RP. 1977. The effect of methemoglobin on the inhibition of cytochrome c oxidase by cyanide, sulfide or azide. Biochem Pharmacol 26 2247-2250. 

FIGURE 8.9 Mitochondrial 02 and H2S consumption from non-limiting 02 to anoxic conditions, (a) Isolated mitochondria were exposed to repeated bouts of 12.5 pM H2S until anoxia was achieved, (b) At higher 02 levels, both 02 and H2S consumption events are coincident, but as the 02 levels decline the events become uncoupled and 02 consumption is limited first. The multiphasic kinetics of 02 consumption may result from transient inhibition of cytochrome c oxidase by H2S. Under anoxia, H2S consumption continues at a low level (after [36] reproduced with permission of the Company of Biologists). 

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). 

In addition to binding to cytochrome c oxidase, cyanide inhibits catalase, peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, and succinic dehydrogenase activities. These reactions may make contributions to the signs of cyanide toxicity (Ardelt et al. 1989 Rieders 1971). Signs of cyanide intoxication include an initial hyperpnea followed by dyspnea and then convulsions (Rieders 1971 Way 1984). These effects are due to initial stimulation of carotid and aortic bodies and effects on the central nervous system. Death is caused by respiratory collapse resulting from central nervous system toxicity. 

Another type of inhibitor combines with the enzyme at a site which is often different from the substrate-binding site and as a result will inhibit the formation of the product by the breakdown of the normal enzyme-substrate complex. Such non-competitive inhibition is not reversed by the addition of excess substrate and generally the inhibitor shows no structural similarity to the substrate. Kinetic studies reveal a reduced value for the maximum activity of the enzyme but an unaltered value for the Michaelis constant (Figure 8.7). There are many examples of non-competitive inhibitors, many of which are regarded as poisons because of the crucial role of the inhibited enzyme. Cyanide ions, for instance, inhibit any enzyme in which either an iron or copper ion is part of the active site or prosthetic group, e.g. cytochrome c oxidase (EC 1.9.3.1). 

Mitochondrial function. NO is able to react with transition metals such as iron, including those contained within haem groups. Even at low NO concentrations there is competition between oxygen and NO for reversible binding to cytochrome c oxidase. If mitochondrial 02 is low respiration slows, which may confer anti-apoptotic benefit to the cell. As NO concentration rises and peroxynitrite is formed, electron transport is irreversibly inhibited, there is increased production of superoxide and other reactive oxygen species and apoptosis occurs. 

The electron transport chain is vital to aerobic organisms. Interference with its action may be life threatening. Thus, cyanide and carbon monoxide bind to haem groups and inhibit the action of the enzyme cytochrome c oxidase, a protein complex that is effectively responsible for the terminal part of the electron transport sequence and the reduction of oxygen to water. 

A number of toxicological mechanisms have been proposed for hydrogen sulfide At extremely high concentrations it may exert a direct paralyzing effect on respiratory centers hydrogen sulfide is also known to inhibit cytochrome c oxidase, resulting in altered oxidative metabolism it can also disrupt critical disulfide bonds in essential cellular proteins. ... 

The toxic potential of methyl mercaptan is due to its reversible inhibition of cytochrome c oxidase at the end of the respiratory chain of mitochondria. ... 

Mitochondrial ATPase inhibition. Smoke extract, in the mouse brain mitochondria culture in the presence or absence of vitamin C for 60 minutes, inhibited mitochondrial ATPase and cytochrome C oxidase activities in a dose-dependent manner. The effect of extract on mitochondria swelling response to calcium stimulation was dependent on calcium concentrations. The extract treatment induced mitochondrial inner membrane damage and vacuolization of the matrix, whereas the outer mitochondrial membrane was preserved. Nicotine produced no significant damage . Mitogenic activity. Water extract of the dried leaf, administered to mice at a concentration of 0.05%, was active on lymphocytes from mesenteric lymph node and lymphocytes B and T. Intracellular Ca level was unchanged. The extract was active on... 

In addition to aconitases, nitric oxide is an inhibitor of many other enzymes such as ribonucleotide reductase [71], glutathione peroxidase [72,73], cytochrome c oxidase [74], NADPH oxidase [75], xanthine oxidase [76], and lipoxygenase [77] but not prostaglandin synthase [78]. (Mechanism of lipoxygenase inhibition by nitric oxide is considered in Chapter... 

Interactions between NO and ferric hemes also result in reversible inhibition of cytochrome P450, catalase, and cytochrome c oxidase activity (66-68), through occupation of the active site and consequent competitive hindrance of mitochondrial respiration. 

The higher stability of ferrous heme nitrosyl complexes compared to the corresponding ferric species is well documented [see Refs (44-46, 69) for reviews]. Since cytochrome P450, catalase, and cytochrome c oxidase are commonly associated with reducing agents, a mechanism exists for longer term inhibition of the activity of these proteins. 

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