Hydroxylation cytochrome P450 biotransformations

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

The numerous biotransformations catalyzed by cytochrome P450 enzymes include aromatic and aliphatic hydroxylations, epoxidations of olefinic and aromatic structures, oxidations and oxidative dealkylations of heteroatoms and as well as some reductive reactions. Cytochromes P450 of higher animals may be classified into two broad categories depending on whether their substrates are primarily endogenous or xenobiotic substances. Thus, CYP enzymes of families 1-3 catalyze... 

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

PE-free callus from Polypodium vulgare was shown to biotransform ecdysone fo 20-hydroxyecdysone, which is the last step in the biosynthetic pathway of the main plant PE. This hydroxylation is catalysed by a cytochrome P450 enzyme which was subsequently purified from that source (Canals et al, 2005). In another study, Reixach et al. (1999) have shown that 25-deoxy-20-hydroxyecdysone was transformed efficiently in both tissues into 20-hydroxyecdysone, but no 25-deoxyecdysteroids such as pterosterone and inokosterone were formed. Likewise, incubation of 2-deoxyecdysone produced exclusively ecdysone and 20E, indicating a high 2-hydroxylase activity in both tissues. 

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). 

Figure 43-1 I Schematic view of the role of NAT enzymes in the metabolism of aromatic amines. N-acetylation might be a detoxification reaction in a number of cases however, after N-hydroxylation of aromatic amines (e.g., by CYP enzymes), NAT enzymes can bioactivate these intermediates by either 0-acetylation or intramolecular N,0-acety transfer, leading to the formation of nitrenium ions, which might react with DNA or alternatively be detoxified by, for example, GST enzymes. Importantly, it is shown that a number of other biotransformation enzymes are also involved in the metabolism of aromatic amines as well. (Redrawn from Wormhoudt LW, Commandeur jNM, Vermeuien NPE. Genetic polymorphisms of human N-acetyitransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes relevance to xenobiotic metabolism and toxicity. Crit Rev Toxicol 1999 29 59-124. Reproduced by permission from Taylor and Francis, Inc.)...

Mirtazapine undergoes biotransformation via demethylation and hydroxylation followed by glucuronide conjugation. The 1A2 and the 2D6 isoenzymes of the cytochrome P450 system may be responsible for the formation of the hydroxymetabolite, whereas the 3A4 isoenzyme may be responsible for the formation of the A-desmethyl and the A-oxide metabolite. Although these metabolites are... 

For the enantioselective preparations of chiral synthons, the most interesting oxidations are the hydroxylations of unactivated saturated carbons or carbon-carbon double bonds in alkene and arene systems, together with the oxidative transformations of various chemical functions. Of special interest is the enzymatic generation of enantiopure epoxides. This can be achieved by epoxidation of double bonds with cytochrome P450 mono-oxygenases, w-hydroxylases, or biotransformation with whole micro-organisms. Alternative approaches include the microbial reduction of a-haloketones, or the use of haloperoxi-dases and halohydrine epoxidases [128]. The enantioselective hydrolysis of several types of epoxides can be achieved with epoxide hydrolases (a relatively new class of enzymes). These enzymes give access to enantiopure epoxides and chiral diols by enantioselective hydrolysis of racemic epoxides or by stereoselective hydrolysis of meso-epoxides [128,129]. 

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