Arene oxides hydration

Another class of potentially toxic compounds are catechols which may be formed either from phenols by secondary hydroxylation or by dehydrogenation of dihydrodiols resulting from enzymatic or spontaneous arene oxide hydration. The reactive species from catechols could be quinoid or semiquinoid oxidation products 38)... 

Diol epoxides. Structural considerations. Because enzymatic hydration of arene oxides produces trans dihydrodiols in mammalian cells, there are two diastereomeric series of diol epoxides. In... 

Jerina, D. M., Dansette, P. M., Lu, A. Y. H., and Levin, W. Hepatic microsomal epoxide hydrase a sensitive radiometric assay for hydration of arene oxides of carcinogenic aromatic hydrocarbons. Mol. Pharmacol. (1977) 13 342-351. 

This chapter begins, thus, with a short introduction to the chemical reactivity of epoxides. We continue with a description of the epoxides hydrolases and their biochemistry, and devote most of its length to a systematic discussion of the substrates hydrated by these enzymes. Arene oxides and diol epoxides will be presented first, followed by a large variety of alkene and cy-cloalkene oxides. 

The microsomal epoxide hydrolases (microsomal EH, mEH), predominantly found in the endoplasmic reticulum, regio- and stereoselectively catalyze the hydration of both alkene and arene oxides, including oxides of polycyclic aromatic hydrocarbons. These enzymes have been purified to homogeneity from various species and tissues [22] [41 - 46], The human microsomal EH contains 455 amino acids (Mr 52.5 kDa) and is the product of the EPHX1 gene [47] (also known as HYL1 [48]). 

Together with glutathione conjugation, hydration is a major pathway in the inactivation and detoxification of arene oxides. Exceptions to this rule will be treated when discussing polycyclic aromatic hydrocarbons. Arene oxides are good substrates for microsomal EH, as evidenced in Table 10.1, where hydration of selected arene oxides, alkene oxides, and cy-cloalkene oxides by purified rat liver epoxide hydrolase is compared. The hy- ... 

As explained in the Introduction, alkene oxides (10.3) are generally chemically quite stable, indicating reduced reactivity compared to arene oxides. Under physiologically relevant conditions, they have little capacity to undergo rearrangement reactions, one exception being the acid-catalyzed 1,2-shift of a proton observed in some olefin epoxides (see Sect. 10.2.1 and Fig. 10.3). Alkene oxides are also resistant to uncatalyzed hydration, thus, in the absence of hydrolases enzymes, many alkene oxides that are formed as metabolites are stable enough to be isolated. 

W. Levin, D. P. Michaud, P. E. Thomas, D. M. Jerina, Distinct Rat Hepatic Microsomal Epoxide Hydrolases Catalyze the Hydration of Cholesterol 5,6a-Oxide and Certain Xenobiotic Alkene and Arene Oxides , Arch. Biochem. Biophys. 1983, 220, 485 - 494. 

HYDRATION WATER a-L-ARABINOFURANOSIDASE d-ARABINOKINASE ARABINONATE DEHYDRATASE ARABINOSE ISOMERASE ARABINOSE-5-PHOSPHATE ISOMERASE Arachidonate 5-lipoxygenase, 5-LIPOXYGENASE ARACHIDONYL-CoA SYNTHETASE Arene oxide intermediate,... 

As has been stated before, oxirane derivatives are formed as intermediates during metabolic oxidations at carbon-carbon double bonds. These epoxides (arene oxides) undergo spontaneous isomerization to phenols, or enzymic hydration via epoxide hydrase to trans- dihydrodiols, or reaction with reduced glutathione (GSH) via specific GSH-transferases to the corresponding conjugates (Scheme 11), which eventually appear in urine... 

Phenanthrene is transformed to trans-9,10- (major), trans-1,2- (minor), and trans-3,4-dihydrodiol (minor) metabolites via monooxygenase-catalyzed formation of arene oxides, followed by epoxide hydrolase-catalyzed hydration in mammalian liver systems.219-221 In bacterial cultures, phenanthrene is converted to cis-3,4- (major) and cis-1,2- dihydrodiols (minor) through the action of dioxygenase enzymes and molecular oxygen.221,222 Recently, Boyd et al.10 have prepared trons-3,4-dihydroxy-1,2,3,4-tetrahydrophenanthrene (359) and cis-3,4-dihydroxy-1,2,3,4-tetrahydrophenanthrene (360) in optically pure forms. These compounds have made possible the determination of the configurations of the trans- and cis-3,4-dihydrodiol metabolites of phenanthrene (361 and 362) as (-)-(3R,4R) and ( + )-(3S,4R), respectively. 

The inwitro metabolites of chlorobenzene are o-chlorophenol, m- chlorophenol, and p-chlorophenol the proportions differ according to the source of the mono-oxygenase system and its state of purity (Selander et al. 1975). The o- and p-chlorophenols result from isomerization of the intermediate 3-and 4-chlorobenzene oxides, respectively. The formation of m-chlorophenol appears to occur via a direct oxidative pathway (Oesch et al. 1973). In vitro conjugation of the arene oxide with glutathione or hydration is not a significant pathway (Selander et al. 1975). 

In general, K-region arene oxides behave rather like aliphatic epoxides and thus readily undergo hydration reactions, whereas benzene oxides and non-K-region arene oxides form dihydrodiols much more reluctantly. Kinetic studies of the mechanism of solvolysis of phenanthrene 9,10-oxide 2 have been carried out in several laboratories.Below pH 7 the hydrolysis reaction was acid-catalyzed and the products included the trans- and c/s-9,10-dihydrodiols along with a preponderance of 9-phenanthrol, while above pH 7 the reaction proceeded via the spontaneous mechanism ( o) mainly the frans-dihydrodiol. 

The term dihydrodiol is widely used in reference to vicinal dihydroxydihydro-derivatives of aromatic hydrocarbons. Although most known and potential benzene oxide or substituted benzene oxide metabolites tend to be quite unstable, a recent study has described the isolation of a relatively stable arene oxide metabolite of 2,2, 5,5 -tetrachlorobiphenyl. Perhaps because of the generally high susceptibility of benzene oxide 1 and many substituted benzene oxides to isomerize to phenols, relatively little has been reported on the kinetics and regiospecificity of their microsomal epoxide hydrolase (EC 3.3.2.3) catalyzed trans hydration to dihydro-... 

The primary goal of initial studies of the microsomal and purified epoxide-hydrolase catalyzed hydration of arene oxides of polycyclic aromatic hydrocarbons was an attempt to identify structure-activity relationships. To this end, some selected values for the hydration of a series of arene oxides are given in Table 2. One of the more obvious aspects of this study was that there is no apparent relation-... 

Armstrong, R. N., Levin, W., and Jerina, D. M. (1980). Hepatic Microsomal Epoxide Hydrolase. Mechanistic Studies of the Hydration of K-Regton Arene Oxides, /. Bio/. Chem., 255 4698-4705. 

Two extremely imponunt enzymatic reactions also aid in nentralizing the reactivity of arene oxides. The First of these involves the hydration (i.c.. nucleophilic attack of water on the epoxide) of arene oxides to yield inactive rra/i.v-dihy-drodiol metabolites (Fig. 4-5). This reaction is catalyzed hy... 

The metabolic oxidation of otefinic carbon-carbon double bonds leads to the corresponding epoxide (or oxiranc). Epoxides derived from olefins generally tend to be somewhat more stable than the arene oxides formed from aromatic-compounds. A few epoxides arc stable enough to be direclly mcasurable in biological fluids (e.g.. plasma, urine). Like their arene oxide counterparts, epoxides- are susceptible to cnz.ymatic hydration by epoxide hydra.se to form lran,s-. 2-dihydrodiols (al.so called 1,2-diols or 1.2-dihydroxy com-... 

Another important group of hydrolytic enzymes are the epoxide hydrolases, also known as epoxide hydrase or epoxide hydratase, most commonly found in liver tissue. Epoxide hydrolases catalyze the hydration of arene oxides and aliphatic epoxides to their corresponding /raKt-dihydrodiols or diols, respectively, by activating a water molecule to attack one of the carbons of the arene oxide or epoxide [41]. Although one of the major metabolites of carbamazepine is the stable epoxide, this metabolite also undergoes hydrolysis to form the trans-dial metabolite (Fig. 3). Likewise, the anticonvulsants phenytoin and mephenytoin form arene oxides, which then form trans-dihy-drodiol that undergo further oxidation to form the catechols by the enzyme dihydrodiol dehydrogenase (Fig. 11) [42,43]. 

Hydrolases catalyze the addition of a molecule of water to a variety of functional moieties. Thus, epoxide hydrolase hydrates epoxides to yield trans-dihydrodiols (reaction 1-B in Fig. 13.5). This reaction is documented for many arene oxides, particularly metabolites of aromatic compounds, and epoxides of olefins. Here, a molecule of water has been added to the substrate without loss of a molecular fragment, therefore the use of the term "hydration" sometimes found in the literature. 

The epoxide hydrolases (EHs ECS.3.2.3) hydrate simple epoxides to vicinal diols, and they hydrate arene oxides to trans-dihydrodiols (also see Table 8.1). 

In humans a microsomal form of EH (mEH) is also found. mEH can catalyze trans-hydration of epoxides and arene oxides yielding reactive diol-epoxides. Xenobiotic substrates include carcinogenic polycyclic aromatic hydrocarbons (PAHs). Whereas diol-epoxide products tend to be highly reactive and carcinogenic or mutagenic, mEH can catalyze the detoxification of xenobiotics as well. 

Hydrates simple epoxides and arene oxides to more polar vicinal diols and tra/w-dihydrodiols... 

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