Cytochromes P450, oxidation

Reduced cytochrome P450 Oxidized cytochrome P450... 

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. 

Epoxide metabolites can be generated from a variety of aromatic systems. Anticonvulsants are a class of drug whose side-effects, such as hepatic necrosis and aplastic anaemia, are thought to be mediated by chemically reactive epoxide metabolites formed by cytochrome P450 oxidation. For instance phenytoin (Figure 8.6) toxicity is correlated with oxidation and the inhibition of epoxide hydrolase [8]. 

Metabolism/Excretion - Nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. 

Scheme 9.2. Conversion of losartan to its active metabolite EXP 3174 by cytochrome P450 oxidation.

Scheme 13.3 Olefinic compounds that form mutagenic epoxides by cytochrome P450 oxidation.

Figure 1. Proposed metabolic pathways of dichloroacetylene by glutathione conjugate formation and cytochrome P450 oxidation...

Zhang R, Nagraj N, Lansakara-P DSP, Hager LP, Newcomb M (2006) Kinetics of Two-Electron Oxidations by the Compound I Derivative of Chloroperoxidase, A Model for Cytochrome P450 Oxidants. Org Lett 8 2731... 

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. 

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. 

The distribution of metabolic functions within acinar zones is determined principally by the microenvironment of the hepatocytes. Cells in zone 1 are the first to respond to changes in the portal blood, such as glucose and insulin levels, and therefore play important roles in glycolysis and gluconeogenesis. Protein synthesis, P-oxidation of fatty acids, cholesterol synthesis and bile acid secretion also predominate in zone 1. Ordinarily zone 3 hepatocytes are the principal site of cytochrome P450 oxidation/reduction activity as well as NADPH and NADH reductase metabolism, making this region more susceptible... 

Next, we evaluated the metabolic rates of compound 7 derivatives, which had a substituent in the indole benzene ring (15-28 Table 7) [6]. Introduction of an electron-withdrawing substituent into the indole moiety tended to suppress the metabolism of a compound (16, 18, 19, 21-23, 27). On the other hand, an electron-donating substituent tended to enhance the metabolism of a compound (20, 26, 28). These observations suggested that the electron density around the indole moiety was correlated to the cytochrome P450 oxidative metabolic rate. In addition, the position of substitution was important. For example, blocking at the 8 -position suppressed the metabolism more effectively than blocking at the 7 - or 9 -positions. 

Figure 24 Polymerized vesicles made of the surfactant (26) and containing the membrane-bound manganese(lll) porphyrin (25) were used by Nolte and coworkers to mimic cytochrome P450 oxidation of alkenes. The vesicles contain colloidal platinum in the internal water pool. Within the microreactor H2 and O2 are converted to H2O and the alkene is epoxidized [89]. MB denotes membrane-bound methylene blue (27)...

The key to many of these degradation processes is oxidative metabolism by the cytochrome P450 enzyme family [10]. Cytochrome P450 oxidation is most easy for electron-rich -electron systems, for example aromatic moieties or olefinic substructures, from which epoxides are generated. These epoxides are often potent electrophiles, intercalating into DNA and reacting with all kinds of nucleophile, for example nucleobases, amines, or thiols. Metabolic processes like this are the reason for the mutagenicity of many polycyclic arenes. 

In contrast, the sex pheromone of the female housefly is (Z)-9-tricosene, a hydrocarbon apparently formed by an oxidative decarboxylative process from a precursor aldehyde by an enzyme that requires NAD-PH and O2 and is apparently a cytochrome P450. ° Oxidative deformylation by a cytochrome P450 converts aldehydes to alkenes, presumably via a peroxo intermediate. Formation of an alkene by decarboxylation has also been proposed, but a mechanism is not obvious. 

Hold, K.M., N.S. Sirisoma, and J.E. Casida (2001). Detoxification of a- and P-thujones (the active ingredients of absinthe) Site specificity and species differences in cytochrome P450 oxidation in vitro and in vivo. Chem. Res. Toxicol. 14, 589-595. 

The endoplasmic reticulum (ER) is a network of membranous tubules within the cell consisting of smooth endoplasmic reticulum (SER), which lacks ribosomes, and rough endoplasmic reticulum (RER), which is studded with ribosomes (Eig. 10.23). The SER has a number of functions. It contains enzymes for the synthesis of many lipids, such as triacylglycerols and phosphohpids. It also contains the cytochrome P450 oxidative enzymes involved in metabohsm of drugs and toxic chemicals such as ethanol and the synthesis of hydrophobic molecules such as steroid hormones. Glycogen is stored in regions of liver cells that are rich in SER. 

They all contain cytochrome P450, oxidize the substrate, and reduce oxygen. 

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