Cytochrome P450 CYP monooxygenases

Several enzymatic systems are involved during the oxidative transformations of xenobiotics. Whether substances act upon one enzyme rather than another depends not only on its specific function, but also on the electromolecular environment. The most important is the microsomal drug metabolizing system known as cytochrome P450 (CYP) monooxygenase, which is localized mainly in the liver and is involved in most biological oxidations of xenobiot-... 

FIGURE 33.2 Catalytic cycle of cytochrome P450 (CYP) monooxygenase. 

Microsomal cytochrome P450 (CYP) monooxygenases are better known for their role in xenobiotic metabolism, a process which is crucial in the therapeutic and toxic effects associated with pharmaceuticals. However, they are also involved in the biosynthetic transformation of PUFA to epoxy-, mono-hydroxylated- and di-hydroxylated-metabolites. When AA is the substrate, CYP-reactions produce a range of epoxyeicosatrienoic acids (EET), hydroxyeicosatrienoic acids (HETE), and dihydroxyeicosatrienoic acids (DHET) (Eigure 3.5). 

Monooxygenation of xenobiotics are catalyzed either by the cytochrome P450 (CYP)-dependent monooxygenase system or by flavin-containing monooxygenases (FMO). 

Epoxidation and hydroxylation A-Dealkylation O-Dealkylation -Dealkylation -Oxidation A-Oxidation P-Oxidation Desulfuration Dehalogenation Nitro reduction Azo reduction Cytochrome P450 (CYP) Aflatoxin, aldrin, benzo[a]pyrene, bromobenzene, naphthalene Ethylmorphine, atrazine, dimethylnitrocarbamate, dimethylaniline p-Nitroanisole, chlorfenvinphos, codeine Methylmercaptan Thiobenzamide, phorate, endosulfan, methiocarb, chlorpromazine 2-Acetylaminofluorene Diethylphenylphosphine Parathion, fonofos, carbon disulfide CCLt, CllCb Nitrobenzene O-Aminoazotoluene Flavin-Containing Monooxygenase (FMO)... 

Monooxygenations are those oxidations in which one atom of molecular oxygen is reduced to water while the other is incorporated into the substrate. Microsomal monooxygenation reactions are catalyzed by nonspecific enzymes such as the flavin-containing monooxygenases (FMOs) or the multienzyme system that has cytochrome P450s (CYPs) as the terminal oxidases. 

Phase I oxidation generally is described as the addition of an oxygen atom (e.g., as an hydroxyl moiety) to the parent molecule. Phase I oxidation is carried out by multiple enzyme pathways, including the various isoforms of the cytochrome P450 (CYP) family and the non-P450 biotransformation enzymes such as flavin-containing monooxygenase (FMO) and monamine oxidase (MAO). 

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