Epoxidation 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... 

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.)...

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]. 

Cytochrome P450 enzymes are the most widespread, active, and most versatile in their xenobiotic Phase I transformation activity. These enzymes are composed of heme-containing enzymes in the ferric ion state. In transformations the ferric ion is reduced to the ferrous ion that can bind Oj and CO. These enzymes basically add oxygen or remove hydrogen in a step-wise process to generate Phase I biotransformation products. Most cytochrome P450 transformations require an additional enzyme (co-enzyme) to assist in the transfer of electrons. Cytochrome P-450 enzymes carry out many kinds of oxidations - hydroxylations, epoxidations, heteroatom oxidations, N-hydroxylations, dealkylations, ester hydrolysis, and dehydrogenation. 

To estimate the health risks represented by brominated flame retardants, it is important to consider, in addition to assessment of the potential routes of exposure, the biotransformation of these compounds in the body. The most abundant congener BDE 47 (2,2, 4,4 -tetrabromodiphenylether) occurring in biotic materials is absorbed up to 95% in the gastrointestinal tract of mice, distributed to the tissues and slowly metabolised. Only a small amount is excreted via excrements. Similarly, as in the case of aromatic xenobiotics, by the action of cytochrome, P450 complex epoxides are produced as the primary products, which, on hydrolysis, yield the corresponding hydroxy derivatives (Figure 12.52). 

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