Phase I reactions oxidative

Specific examples of phase I oxidative reactions are shown in Figure 6.29. 

As with adults, the primary organ responsible for drug metabolism in children is the liver. Although the cytochrome P450 system is fully developed at birth, it functions more slowly than in adults. Phase I oxidation reactions and demethylation enzyme systems are significantly reduced at birth. However, the reductive enzyme systems approach adult levels and the methylation pathways are enhanced at birth. This often contributes to the production of different metabolites in newborns from those in adults. For example, newborns metabolize approximately 30% of theophylline to caffeine rather than to uric acid derivatives, as occurs in adults. While most phase I enzymes have reached adult levels by 6 months of age, alcohol dehydrogenase activity appears around 2 months of age and approaches adult levels only by age 5 years. 

The NADPH-cytochrome P-450 system, commonly known as the mixed-function oxygenase (MFO) system, is the most important enzyme system involved in the Phase I oxidation reactions. Cytochrome P-450 system, localized in the smooth endoplasmic reticulum of cells of most mammalian tissues, is particularly abundant in the liver. This system contains a number of isozymes which are versatile in that they catalyze many types of reactions including aliphatic and aromatic hydroxylations and epoxidations,... 

The metabolism of xenobiotics in higher plants has been studied extensively over the last 20 years. In common plant species such as corn, it is frequently possible to predict the conjugation reactions that may be utilized in the initial phases of metabolism of a new xenobiotic. In less commonly studied species, predictions are more uncertain and exotic metabolites sire occaslonaly formed. In those cases where phase I oxidative reactions are likely, it is difficult to predict the course of metabolism because phase I oxidation reactions in plants are frequently very substrate and species specific. Phase I oxidative reactions have a profound effect on ensuing conjugation reactlcxis. The presence of multiple functional groups on a xenobiotic also Increases the uncertainty of the route of metabolism likely to be followed in a particular species. 

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. 

The hydroxylation or oxidation of heterocyclic atoms (i.e., nitrogen) is a common phase I oxidative reaction. The metabolites generated by the oxidation at the N atom are known as N-oxides. Several N-oxides are reported to be carcinogenic and/or to exhibit toxicological effects (Sugimura et al., 1966 Bosin and Maickel, 1973 Kiese et al. 1966). Chowdhury and co-workers demonstrated the application of LC APCI MS(/MS) to distinguishing N-oxide metabolites from hydroxylated metabolites (Ramanathan et al., 2000 Tong et al., 2001). 

Propylene oxide is also produced in Hquid-phase homogeneous oxidation reactions using various molybdenum-containing catalysts (209,210), cuprous oxide (211), rhenium compounds (212), or an organomonovalent gold(I) complex (213). Whereas gas-phase oxidation of propylene on silver catalysts results primarily in propylene oxide, water, and carbon dioxide as products, the Hquid-phase oxidation of propylene results in an array of oxidation products, such as propylene oxide, acrolein, propylene glycol, acetone, acetaldehyde, and others. 

Phase I metabolic reactions involve oxidation, reduction, or hydrolysis of the parent molecule, resulting in the formation of a more polar compound. Phase 1 reactions are mediated by the cytochrome P450 (GYP) family of enzymes. While metabolism used to be thought of as the body s detoxification process, phase I metabolites may be equally or even more pharmacologically active than the parent compound. Drug metabolism in general, and CYP-based mechanisms in particular, are discussed in detail in Chapter 5. 

Oxidation is by far the most important Phase I metabolic reaction. One of the main enzyme systems involved in the oxidation of xenobiotics appears to be the so called mixed function oxidases or monooxygenases, which are found mainly in the smooth endoplasmic reticulum of the liver but also occur, to a lesser extent, in other tissues. These enzymes tend to be nonspecific, catalysing the metabolism of a wide variety of compounds (Table 9.2). Two common mixed function oxidase systems are the cytochrome P-450 (CYP-450) and the flavin monoxygenase (FMO) systems (Appendix 12). The overall oxidations of these systems take place in a series of oxidative and reductive steps, each step being catalysed by a specific enzyme. Many of these steps require the presence of molecular oxygen and either NADH or NADPH as co-enzymes. 

Biotransformation of xenobiotics takes place in two phases. In phase I (= functionalization reactions), reactive groups are either activated or inserted into the substance molecule, thus providing the lipophilic molecule with a functional hydrophilic group. (In phase II, a hydrophilic residue is added to this group transferases hereby catalyze the conjugation with an endogenous substance.) Phase I elfects the insertion of reactive (polar) groups (such as -OH, -COOH, -SH, -NH2) by means of four chemical processes oxidation, reduction, hydrolysis, and hydration. 

With the idea of avoiding the potential bimolecular coupling reaction of the radical centers in the solution-phase chemical oxidation reactions, a photochemical approach was adopted. Diazo compounds 10 and 12 were treated with the Rh catalyst under basic conditions to give the poly(acetylene)s 43 [R and m- /7-(/i-C,9H39)C6H4]C(N2)] of 200000 [8]. While photolysis of the diazo groups proceeded smoothly on neat films at 2 K and broad EPR si-... 

Foreign compounds may be metabolized by non-microsomal enzyme systems. These reactions include deamination of amines, oxidation of alcohols and aldehydes, reduction of aldehydes and ketones, hydrolysis of some esters and amides and may occur in the mitochondria, or the cell supernatant fraction, or in the circulating plasma. A thorough discussion of these non-microsomal mechanisms has been presented by Parke [20], These reactions are confined to Phase I oxidations, reductions, and hydrolyses (see Fig. 1). 

Wachs, I., Jehng, J., Deo, G., et al. (1996). In Situ Raman Spectroscopy Studies of Bulk and Surface Metal Oxide Phases during Oxidation Reactions, Catal. Today, 32, pp. 47-55. Guliants, V, Benziger, J., Sundaresan, S., et al. (1995). Evolution of the Active Surface of the Vanadyl Pyrophosphate Catalysts, Catal. Lett., 32, pp. 379-386. 

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