Cytochrome reactive intermediated

To this end, cytochrome P-450 may be considered as nature s equivalent of Fenton s reagent in the enzyme system, highly reactive intermediates such as hydroxyl radicals and oxenes appear to be controlled by their interaction with hemoprotein. 

Bumpus, N.N. (2008) Mechanism-based inactivation of human cytochromes p450s e5q)erimental characterization, reactive intermediates, and clinical implications. Chemical Research in Toxicology, 21,189—205, Epub 2007 Dec 4. 

Azri S, Mata HP, Gandolfi AJ, Brendel K. 1991. CCKinduced cytochrome P-450 loss and lipid peroxidation in rat liver slices. Biol Reactive Intermediates 669-674. 

Metabolism of TCDD. No metabolites of TCDD have been identified so far. It has recently been reported by Guenthner et al.(20) that TCDD can be metabolized by the mouse liver cytochrome P-U50 system to reactive intermediates, which easily bind covalently to cullular proteins. It is suggested that this extreme reactivity inhibits the formation of normal metabolites like phenols, dihydrodiols, or conjugated products. ... 

Oxidative dehalogenation. Halogen atoms may be removed from xenobiotics in an oxidative reaction catalyzed by cytochromes P-450. For example, the anesthetic halothane is metabolized to trifluoroacetic acid via several steps, which involves the insertion of an oxygen atom and the loss of chlorine and bromine (Fig. 4.28). This is the major metabolic pathway in man and is believed to be involved in the hepatotoxicity of the drug. Trifluoroacetyl chloride is thought to be the reactive intermediate (see chap. 7). 

Various enzymes can produce reactive intermediates by metabolism, especially cytochrome P-450, but also peroxidases, FMO, prostaglandin synthetase, MAO. 

It should be noted that acetylhydrazine can also be further metabolized to an electrophilic reactive intermediate by cytochrome P-450. This will be discussed in detail in chapter 7. 

Metabolic activation via cytochromes P-450 to reactive metabolites. A reactive intermediate has been suggested as some inhibitors of cytochromes P-450 decrease the toxicity, and some inducers of the monooxygenases increase toxicity. However, other inducers and inhibitors do not change toxicity, and these treatments also affect the renal concentration of cephaloridine in a manner consistent with the effect on toxicity. As the p-lactam ring is unstable, a chemical rearrangement to produce a reactive intermediate is also possible. 

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. 

Fev=0 and Mnv=0 have also recently emerged as plausible reactive intermediates in the oxidation of hydrocarbons by iodosylbenzene, amine N-oxide, percarboxylic acids, hypochlorites, etc. catalyzed by iron or manganese porphyrins. Current opinion favors Fev=0 species as the active oxidant in cytochrome P-450 monooxygenases.54 55... 

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