CYP monooxygenase

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-... 

Those include C-, N- and 5-oxidations, N-, 0- and 5-deaIkylation, deaminations, and certain dehalogenations. Under anaerobic conditions, it can also catalyze reductive reactions. The CYP monooxygenase system is a multien-zymatic complex constituted by the CYP hemoprotein, the flavoprotein enzyme NADPH CYP reductase, and the unsatnrated phospholipid phosphatidylcholine. The isoforms involved in xenobiotic metabolism are membrane bonnd enzymes situated in the endoplasmic reticnlnm. After... 

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

These oxidations, which are usually catalyzed by CYP monooxygenases, produce hydroxylated derivatives. When the C-H bond is located in the a position to a heteroatom (such as O, S, N, halogen), the a hydroxylated derivative obtained is usually unstable and may be further oxidized or cleaved (Figure 33.5). 

The antibiotic chloramphenicol is oxidized by CYP monooxygenase to chloramphenicol oxamyl chloride formed by the oxidation of the dichloromethyl moiety of chloramphenicol followed by elimination of hydrochloric acid " (Figure 33.6). The reactive metabolite reacts with the e-amino group of a lysine residue in CYP and inhibits the enzymatic reaction progressively with time. This type of inhibition is a time-dependent inhibition or a mechanism-based inhibition or inactivation, and the substrate involved historically has been called a suicide substrate because the enzymatic reaction yields a reactive metabolite, which destroys the enzyme. ... 

Double bonds are oxidized by CYP monooxygenases into epoxides, which are generally very reactive. Epoxides are considered responsible for the toxicity of the unsaturated compounds. 

Halogenated aromatic compounds may also be oxidized by CYP monooxygenases, yielding hypervalent halogenated compounds. 

Tienilic acid is oxidized in the liver by CYP monooxygenase to 5-hydroxytienilic acid, which is the major urinary metabolite (about 50% in human). In humans, the bioactivation of tienilic acid depends on CYP2C9. This isoform is one of the major forms of CYP in the human liver. This oxidation occurs through an electrophilic intermediate capable of alkylating very specifically the leading... 

Halothane is a widely used anesthetic drug that occasionally results in severe hepatitis. About 60-80% of the dose is eliminated in unmetabolized form during the 24 h following administration to patients. This compound is metabolized in the presence of CYP monooxygenase CYP2F1 according to the two main pathways depicted in Figure 33.26. 

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). 

Fig. 13.2 Arachidonic acid (AA) is metabolized by cy- form epoxyeicosatrienoic acids (EETs), mid-chain hy-tochrome P450 (CYP) monooxygenases in epoxygenase, droxyeieosatetraenoic acids (HETEs), and co/co-l HETEs, lipoxygenase-like, and co/co-l hydroxylase reactions to respectively...

Acrylamide is metabolised to an 1,2-epoxide by cytochrome P4so-dependent (CYP) monooxygenases. Due to the large ring strain associated with the three-membered ring epoxides are reactive molecules. 

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