Activation by cytochrome

How does nature prevent the release of hydrogen peroxide during the cytochrome oxidase-mediated four-electron reduction of dioxygen It would appear that cytochrome oxidase behaves in the same manner as other heme proteins which utilize hydrogen peroxide, such as catalase and peroxidase (vide infra), in that once a ferric peroxide complex is formed the oxygen-oxygen bond is broken with the release of water and the formation of an oxo iron(IV) complex which is subsequently reduced to the ferrous aquo state (12). Indeed, this same sequence of events accounts for the means by which oxygen is activated by cytochromes P-450. 

Cosulich, S.C., Savory, P.J., and Clarke, P.R., 1999, Bcl-2 regulates amplification ofcaspase activation by cytochrome c, Current Biology 9 147-150. 

Nonmetallic neurotoxins are frequently used in industry in manufacturing of chemicals and resins or as solvents. Some examples are hydrogen sulfide (which paralyzes specifically the nervous centers that control respiratory movement), carbon disulfide, -hexane, methyl -butyl ketone, and acrylamide. Exposure to all of these substances may occur through inhalation of vapors. In addition, carbondisufide and acrylamide may enter the system by dermal absorption. -Hexane and methyl -butyl ketone are not toxic by themselves but are activated by cytochrome P-450 to the neurotoxic hexanedione (CH3COCH2CH2COCH3). 

Thus, the susceptibility is the result of accumulation of the drug in the target organ to reach concentrations not achieved in other tissues. This is then followed by what is probably a combination of events such as formation of a reactive intermediate, possibly a free radical, stimulation of lipid peroxidation and depletion of GSH, and then peroxidative damage to cell membranes and mitochondria. Whether metabolic activation by cytochromes P-450, or chemical rearrangement, or reductive activation, or all the three are involved is not currently clear. 

Vinyl chloride is a chemical used in the manufacture of plastics, which is carcinogenic and causes various toxic effects, including liver injury and damage to the bones and skin. Liver hemangiosarcomas are produced in animals and humans. Vinyl chloride undergoes metabolic activation by cytochrome P-450 to an epoxide, which may interact with DNA and form adducts (ethenodeoxyadenosine and ethenodeoxycytidine), which leads to mutations. These can be detected in white cells, and a mutant p21 ras protein can be detected in the serum of exposed workers. Also, reaction with GSH occurs. 

Both these substituted hydrazine drugs may cause liver damage after therapeutic doses. With isoniazid, a mild hepatic dysfunction may occur in 10% to 20% of patients and a more severe type in less than 1%. Both isoniazid and iproniazid yield hydrazine metabolites (acetylhy-drazine and isopropylhydrazine, respectively), which are responsible for the hepatotoxicity after activation by cytochrome P-450. Isoniazid undergoes acetylation, which in humans is polymorphic. Slow acetylators are more at risk from the hepatotoxicity because acetylhy-drazine is detoxified by acetylation. 

Chloroform is an anesthetic and solvent, which may be nephrotoxic and hepato toxic. It requires metabolic activation by cytochrome P-450, and male mice are more susceptible to the nephrotoxicity than females, which are more likely to suffer hepatic damage. The renal damage, proximal tubular necrosis, is accompanied by fatty infiltration. The metabolic activation, which may take place in the kidney, produces phosgene, which is reactive and can bind to critical proteins. 

Carbon tetrachloride causes centrilobular liver necrosis and steatosis after acute exposure, and liver cirrhosis, liver tumors, and kidney damage after chronic administration. The mechanism underlying the acute toxicity to the liver involves metabolic activation by cytochrome P-450 to yield a free radical (trichloromethyl free radical). This reacts with unsaturated fatty acids in the membranes of organelles and leads to toxic products of lipid peroxidation including malondialdehyde and hydroxynonenal. This results in hepatocyte necrosis and inhibition of various metabolic processes including protein synthesis. The latter leads to steatosis as a result of inhibition of the synthesis of lipoproteins required for triglyceride export. 

Such reactions are interesting as models for oxygen atom transfer in mechanisms of dioxygen activation by cytochrome P450 enzyme systems (49, 50, 51). 

Examples of GDEPT include irinotecan (CPT-11), a prodrug of 7-ethyl- 10-hydroxy-camptothecin activated by carboxylesterase 5-fluorocytosine, a prodrug of 5-FU activated by cytosine deaminase and cyclophosphamide, a prodrug of 4-hydroxycyclophosphamide activated by cytochrome P450, which degrades into acrolein and phospho-ramide mustard.112-115... 

Yamazaki H, Nakajima M, Nakamura M, et al. Enhancement of cytochrome P-450 3A4 catalytic activities by cytochrome b(5) in bacterial membranes. Dmg Metab Dispos 1999 27 999-1004. 

Yeom, H. Y., and Sligar, S. G. 1997 Oxygen activation by cytochrome P450(BM-3) Effects of mutating an active site acidic residue. Arch. Biochem. Biophys., 337, 209-216. 

Coon, M.J., White, R.E., and Blake, R.C. (1981) Oxygen activation by cytochrome P450, in King, T.E. (ed.) Oxidases and related systems, 1, University Park Press, Baltimore, pp. 93-118. 

Activated PKB (Akt) phosphorylates the following proteins with the indicated anabolic consequences Bad phosphorylation yields P-Bad which then dissociates from a Bcl-2-Bcl-X] complex in the mitochondrial outer membrane and is sequestered by 14.3.3 proteins. Mitochondrial pore blockage by the Bad-free Bcl-2-Bcl-xL complex successively prevents cytochrome c release from mitochondria, blocks procaspase activation by cytochrome c and thus inhibits apoptosis and increases cell survival. Phosphorylation of p70S6 kinase by PKB results in activation of this PK, phosphorylation of ribosomal small subunit protein S6 and enhancement of translation (protein synthesis). Phosphorylation of glycogen synthase (GS) kinase 3 (GSK3) by PKB results in an inactive P-GSK3, a consequent increase in the amount of the active non-phosphorylated form of GS and increased glycogen synthesis. 

Figure 27.45. Aflatoxin Reaction. The compound, produced by molds that grow on peanuts, is activated by cytochrome P450 to form a highly reactive species that modifies bases such as guanine in DNA, leading to mutations.

V-PYRRO/NO (liver-selective NO donor (i-GIc-PYRRO/NO activated by cytochrome p450) (stable at pH 7.4 activated... 

Lewis DF, Ioannides C, Parke DV. A quantitative structure-activity relationship (QSAR) study of mutagenicity in several series of organic chemicals likely to be activated by cytochrome P450 enzymes. Teratogen Carcinogen Mutagen 2003 (Suppl)l 187-93. 

Aromatic compounds substituted with amino groups, e.g., heterocyclic aromatic amines present in protein food products, are usually activated by cytochrome P450 to hydroxylamines. This type of metabolism is observed in the case of 3-amino-1-methyl-5//-pyrido[4,3-/ ]indolc (Trp-P-2). 

Ethynyl moieties activated by cytochrome P450 (Fig. 5, reaction 3)... 

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