Oxidation, biotransformation reaction

Species variation has been observed in many oxidative biotransformation reactions. For example, metabolism of amphetamine occurs by two main pathways oxidative deamination or aromatic hydroxylation. In the human, rabbit, and guinea pig. oxidative deamination appears to be the predominant pathway in the rat. aromatic hydroxylation appears to be the more important route. Phenytoin is another drug that shows markeii species differences in metabolism. In the human, phenytoin undergoes aromatic oxidation to yield primarily (5K-)-/r-hydioxyphenytoin in the dog. oxidation occurs to give mainly (If)(-1-)-iM-hydroxyphenyt-oin. There is a dramatic difference not only in the pasition (i.e.. meta or para) of aromatic hydroxylation but also in which of the two phenyl rings (at C-S of phenytoin) undergoes aromatic oxidation. 

Many drugs, such as buspirone, undergo multiple oxidative biotransformation reactions. In cases such as buspirone the secondary metabolites, which are minor metabolites in vitro, are major metabolites in the circulation or excreta in humans and animals because primary metabolites are rapidly converted to secondary metabolites. To determine the formation pathways and structures of secondary or sequential metabolites, a method using metabolite incubation and HPLC MSC MS analysis was developed and demonstrated using buspirone as an example (Zhu, 2002). [ Cjbuspirone was incubated with HLM, and metabolic profiling was carried out using HPLC-MSC. The... 

Biotransformation reactions can be classified as phase 1 and phase 11. In phase 1 reactions, dmgs are converted to product by processes of functionalization, including oxidation, reduction, dealkylation, and hydrolysis. Phase 11 or synthetic reactions involve coupling the dmg or its polar metaboHte to endogenous substrates and include methylation, acetylation, and glucuronidation (Table 1). 

Technical-grade endosulfan contains at least 94% a-endosulfan and (3-endosulfan. The a- and (3-isomers are present in the ratio of 7 3, respectively. The majority of the studies discussed below used technical-grade endosulfan. However, a few examined the effects of the pure a- and (3-isomers. Endosulfan sulfate is a reaction product found in technical-grade endosulfan as a result of oxidation, biotransformation, or photolysis. There is very little difference in toxicity between endosulfan and its metabolite, endosulfan sulfate. However, the a-isomer has been shown to be about three times as toxic as the P-isomer of endosulfan. 

In some cases it is more attractive to use whole microbial cells, rather than isolated enzymes, as biocatalysts. This is the case in many oxidative biotransformations where cofactor regeneration is required and/or the enzyme has low stability outside the cell. By performing the reaction as a fermentation, i.e. with growing microbial cells, the cofactor is continuously regenerated from the energy source, e.g. glucose. 

Although UGTs catalyze only glucuronic acid conjugation, CYPs catalyze a variety of oxidative reactions. Oxidative biotransformations include aromatic and side chain hydroxylation, N-, O-, S-dealkylation, N-oxidation, sulfoxidation, N-hydroxylation, deamination, dehalogenation and desulfation. The majority of these reactions require the formation of radical species this is usually the rate-determining step for the reactivity process [28]. Hence, reactivity contributions are computed for CYPs, but a different computation is performed with the UGT enzyme (as described in Section 12.4.2). 

Hydrolysis of phthalate diesters to the respective monoesters appears to be the first and the major biotransformation reaction in all of these species, but subsequent oxidative metabolism also may occur. 

In general, biotransformation reactions are beneficial in that they facilitate the elimination of xenobiotics from pulmonary tissues. Sometimes, however, the enzymes convert a harmless substance into a reactive form. For example, CYP-mediated oxidation often results in the generation of more reactive intermediates. Thus, many compounds that elicit toxic injury to the lung are not intrinsically pneumotoxic but cause damage to target cells following metabolic activation. A classic example of this is the activation of benzo(a)pyrene, which is a constituent of tobacco smoke and combustion products, and is... 

Oxidative biotransformation provides a commonly reported means of removing alkyl groups from substituted oxygen and nitrogen atoms. These reactions are believed to proceed via monooxygenase-mediated a-hydroxylation of the alkyl group to an unstable hemiacetal or hemiaminal, as outlined in Fig. 4 for an 0-alkyl substituted compound. 

Phase 1 reactions Oxidative reactions involving N- and O-dealkylation, aliphatic and aromatic hydroxylation, N- and S-oxidation, deamination. Phase 2 reactions Biotransformation reactions involving glucuronization, sulphation, acetylation. 

Alkaloids of this group are susceptible to oxidative biotransformations by many microorganisms resulting in N-demethylation, C-hydroxylation, or ring-closure reactions (11). Many of the observed biotransformations parallel or are closely related to processes thought to occur in the normal biosynthesis of the ergot alkaloids and may indeed involve the same or similar enzyme systems to those responsible for the normal production of the alkaloids themselves (11, 64, 65). 

The mechanism in hepatic cellular metabolism involves an electron transport system that functions for many drugs and chemical substances. These reactions include O-demethylation, N-demethyla-tion, hydroxylation, nitro reduction and other classical biotransformations. The electron transport system contains the heme protein, cytochrome P-450 that is reduced by NADPH via a flavoprotein, cytochrome P-450 reductase. For oxidative metabolic reactions, cytochrome P-450, in its reduced state (Fe 2), incorporates one atom of oxygen into the drug substrate and another into water. Many metabolic reductive reactions also utilize this system. In addition, there is a lipid component, phosphatidylcholine, which is associated with the electron transport and is an obligatory requirement for... 

For most drugs, oxidative biotransformation is performed primarily by the mixed-function oxidase enzyme system, which is present predominantly in the smooth endoplasmic reticulum of the liver. This system comprises (1) the enzyme NADPH cytochrome P450 reductase (2) cytochrome P450, a family of heme-containing proteins that catalyze a variety of oxidative and reductive reactions and (3) a phospholipid bilayer that facilitates interaction between the two proteins. Important exceptions to this rule are ethyl alcohol and caffeine, which are oxidatively metabolized by enzymes primarily present in the soluble, cytosolic fraction of the liver. 

Grape compounds which can enter the yeast cell either by diffusion of the undissociated lipophilic molecule or by carrier-mediated transport of the charged molecule across the cell membrane are potentially subject to biochemical transformations by enzymatic functions. A variety of biotransformation reactions of grape compounds that have flavour significance are known. One of the earlier studied biotransformations in yeast relates to the formation of volatile phenols from phenolic acids (Thurston and Tubb 1981). Grapes contain hydroxycinnamic acids, which are non-oxidatively decarboxylated by phenyl acryl decarboxylase to the vinyl phenols (Chatonnet et al. 1993 Clausen et al. 1994). 

The superfamily of P450 cytochrome enzymes is one of the most sophisticated catalysts of drug biotransformation reactions. It represents up to 25% of the total microsomal proteins, and over 50 cytochromes P450 are expressed by human beings. Cytochromes P450 catalyze a ivide variety of oxidative and reductive reactions, and react with chemically diverse substrates. Despite the large amount of information on the functional role of these enzymes combined with the knowledge of their three-dimensional structure, elucidation of cytochrome inhibition, induction, isoform selectivity, rate and position of metabolism all still remain incomplete [6]. 

Of the various pha.se I reactions that are considered in this chapter, oxidative biotransformation processes are, by far. the most common and important in drug metabolism. The general stoichiometry that describes the oxidation of many xenobiutics (R-H) to their corresponding oxidized metabolites (R-OH) is given by the following equation ... 

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