Cytochrome P450 oxidation reactions

In addition to their use for the calibration of rates for radical reactions, radical clocks can be employed to distinguish between ionic and radical pathways. In the simplest embodiment of this idea, a suitable clock reaction that undergoes a known fast rearrangement with easily identifiable products is incorporated into the reaction system to be studied. This approach has been exploited in the pioneering work of Newcomb and co-workers in studies of the mechanism of cytochrome P450 oxidation reactions [13]. Newcomb has developed a range of ultrafast radical clocks able to detect radical species with lifetimes of 80-200 fs. 

Guengerich, F.P. (2003) Cytochrome P450 oxidations in the generation of reactive electrophiles epoxidation and related reactions. Archives of Biochemistry and Biophysics, 409, 59-71. 

Fig. 5.18 Schematic representation of the mechanism of haloperoxidases. In the presence of Cl", HOCI is formed that (a) diffuses from the active site and oxidizes substrates in the medium, although in some cases, (b) oxidation may occur within the active site. In the absence of Cl", thiol-ligated haloperoxidases can (c) catalyze oxygen transfer to their substrates in a cytochrome P450-like reaction...

A. Goldblum and G. H. Loew, / Am. Chem. Soc., 107, 4265 (1985). Quantum Chemical Studies of Model Cytochrome P450 Oxidations of Amines. I. MNDO Pathways for Al-kylamine Reactions with Singlet and Triplet Oxygen. 

A. T. Pudzianowski and G. H. Loew, Int. J. Quantum Chem., 23, 1257 (1983). Mechanistic Studies of Oxene Reactions with Organic Substrates Reaction Paths on MNDO Enthalpy Surfaces—Models for Cytochrome P450 Oxidations. 

Tirapazamine is inactivated by two-electron reduction steps catalyzed by quinone reductase, yielding first the mono-N-oxide (reaction a and compound 18). In contrast, it is activated to a cytotoxic nitroxide (16) by a one-electron reduction catalyzed by NADPH-cytochrome P450 reductase (reaction b). This delocalized radical loses one molecule of water to yield a reactive radical (reaction c and compound 17). Radical 17 can then abstract one hydrogen radical from DNA (reaction d and compound 18), leading to DNA breaks and cytotoxicity. In summary, both inactivation and activation involve reduction reactions, but cytotoxicity will depend on the relative levels of quinone reductase and CYP reductase in hypoxic cells. 

In the MAO-catalyzed reaction, intermediate structure 10 is converted directly to structure 12. As shown in figure 2, the electron acceptor for the cytochrome P450-catalyzed reaction is the perferryl 0X0 species (Fe O), while the electron acceptor for the MAO-catalyzed reaction is the oxidized flavin moiety (FAD). 

Dihydropyridines, and particularly calcium channel blockers such as nivaldipide (7) (Fig. 13.8), are effectively oxidized by cytochrome P450. The reaction is one of aromati-zation (reaction 6 in Fig. 13.7), yielding the corresponding pyridine. 

The benzimidazoles have limited water solubility and, as a result, are poorly absorbed from the Gl tract (a fatty meal will increase absorption). Poor absorption may be beneficial, because the drugs are used primarily to treat intestinal helminths. To the extent that the drugs are absorbed, they undergo rapid metabolism in the liver and are excreted in the bile (Fig. 39.17) (56,57). In most cases, the parent compound is rapidly and nearly completely metabolized with oxidative and hydrolytic processes predominating. The Phase I oxidative reaction commonly is a cytochrome P450-catalyzed reaction, which may then be followed by a Phase II conjugation. 

J. H. (2004) Hydroperoxoferric heme intermediate as a second electrophilic oxidant in cytochrome P450-catalyzed reactions. J. Biol. Inorg. Chem., 9 (6), 644 653. 

The numerous biotransformations catalyzed by cytochrome P450 enzymes include aromatic and aliphatic hydroxylations, epoxidations of olefinic and aromatic structures, oxidations and oxidative dealkylations of heteroatoms and as well as some reductive reactions. Cytochromes P450 of higher animals may be classified into two broad categories depending on whether their substrates are primarily endogenous or xenobiotic substances. Thus, CYP enzymes of families 1-3 catalyze... 

Superoxide is formed (reaction 1) in the red blood cell by the auto-oxidation of hemoglobin to methemo-globin (approximately 3% of hemoglobin in human red blood cells has been calculated to auto-oxidize per day) in other tissues, it is formed by the action of enzymes such as cytochrome P450 reductase and xanthine oxidase. When stimulated by contact with bacteria, neutrophils exhibit a respiratory burst (see below) and produce superoxide in a reaction catalyzed by NADPH oxidase (reaction 2). Superoxide spontaneously dismu-tates to form H2O2 and O2 however, the rate of this same reaction is speeded up tremendously by the action of the enzyme superoxide dismutase (reaction 3). Hydrogen peroxide is subject to a number of fates. The enzyme catalase, present in many types of cells, converts... 

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