Inhibition of cytochrome c oxidase

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). 

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. ... 

Inhibition of cytochrome c oxidase, interaction with phospholipids 358... 

While cyanide inhibition of cytochrome c oxidase may not account for the full spectrum of toxicity in CS exposure, cyanide toxicity may include an array of biochemical interactions (Way, 1984). These include lipid peroxidation (Johnson et al, 1987), cyanide release of endogenous opioids to cause respiratory paralysis (Leung et al, 1986), disruption of neuronal calcium homeostasis (Johnson et al, 1986), and phospholipids hydrolysis (Sakaida and Farber,... 

Kiyomiya K, Matsushita N, Matsuo S, and Kurebe M. Cephaloridine-induced inhibition of cytochrome c oxidase activity in the mitochondria of cultured renal epithelial cells (LLC-PK(I)) as a possible mechanism of its nephrotoxicity.ToxicolAppI Pharmacol... 

The inhibition of cytochrome c oxidase, and resultant disturbance of electron transport, results in decreased mitochondrial O2 utilization and decreased ATP (Olsen and Klein, 1947). Anaerobic metabolism leads to an accumulation of lactic acid and lactate acidosis, and the combination of lactate acidosis and cytotoxic hypoxia causes severe metabolic disturbances, particularly in the central nervous system (CNS), resulting in disturbances of perception and consciousness. 

Cleeter MWJ, Cooper JM, Darley-Usmar VM, Moncada S, Shapira AHV (1994) Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain. Implications for neurodegenerative diseases. FEBS Lett 345 50-54 Poderoso JJ, Carreras MC, Lisdero CL, Riobo NA, Schopfer F, Boveris A (1996) Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles. Arch Biochem Biophys 328 85-92 Ignarro LJ (2000) In Ignarro LJ (ed) Nitric oxide biology and pathobiology. Academic Press, New York... 

These often involve regulation of transcription. As mentioned in Chapter 18, Section F,2, many of the effects of NO are a resulf of activation of soluble gua-nylate cyclase (p. 561). In the endothelium other hormones, such as the endothelins (p. 1750), atrial natriuretic factor, and bradykinin (Box 22-D), cooperate in the regulation of NO synthase. Neuronal NO synthase fimctions in the brain in olfaction and in formation of memory. In the peripheral system it mediates penile erection and plays a variety of roles in the enteric nervous system. Neuronal NO synthase is often localized to synaptic regions by binding to tissue-specific proteins. NO may also regulafe cellular respiration by inhibition of cytochrome c oxidase. ... 

Chen, J., Peterson, D., Schenker, S., and Henderson, G.I. (2000). Eormation of malondialdehyde adducts in fivers of rats exposed to ethanol Role in ethanol-mediated inhibition of cytochrome c oxidase. Alcoholism Clin. Exp. Res. 24(4) 544-552. 

The main function of mtNOS is regulation of the mitochondrial respiration by inhibition of cytochrome C oxidase. This dimeric enzyme is located on the inner membrane of the mitochondrion and... 

Cyanide salts and the colorless gaseous HCN are highly toxic and should be handled with care. The primary toxicity of CN" results from inhibition of cytochrome c oxidase (a key enzyme in the electron transport chain), which catalyzes the four electron reduction of dioxygen to Hp. The cyanide ligand inhibits the enzyme by occupying the binding site on one of the enzyme s iron centers. 

Dihydroorotate dehydrogenase (EC 1.3.99.11) catalyses the oxidation of dihydroorotate to orotate in the pyrimidine biosynthesis pathway. Inhibition of cytochrome c oxidase indirectly inhibits dihydroorotate dehydrogenase activity. In digitonin-permeabilized cells, sodium l,l-diethyl-2-hydroxy-2-nitroso-hydrazine, a chemical nitric oxide donor, induced a dramatic decrease in dihydroorotate-dependent O2 consumption (Beuneu et al. 2000). The inhibition was reversible and more pronounced at low O2 concentration it was correlated with a decrease in orotate synthesis. 

Chandel NS, Budinger GR, Kemp RA, Schumacker PT. Inhibition of cytochrome-c oxidase activity during prolonged hypoxia. Am J Physiol 1995 268 L918-L925. 

Brown GC. Regulation of mitochondrial respiration hy nitric oxide inhibition of cytochrome c oxidase. Biochim Biophys Acta 2001 1504 46-57. 

Phosphine is another chemical asphyxiant agent worthy of mention. This is a colourless and flammable gas, exposure to which causes inhibition of cytochrome C oxidase and mitochondrial oxygen uptake. Symptoms usually occur within the first few hours of exposure. Treatment is essentially the same as that for arsine, relying on supportive measures. 

---