Hydration of epoxides

A priori, H20 would also be expected to act as protective nucleophile against reactive epoxides. Because H20 is a very weak nucleophile [17], the nonenzymatic hydration of epoxides to vicinal diols (10.12, Nu = OH, Fig. 

Yet, despite the relative inertness of H20 and the very low physiological concentrations of the HO ion, hydration of epoxides is known to be a metabolic reaction of both qualitative and quantitative significance. This hydrolysis is mediated physiologically by the epoxide hydrolases, a group of enzymes whose remarkable efficiency and versatility are the main topic of this chapter. 

In earlier chapters, we examined metabolic reactions of hydrolysis, which mainly involve ester and amide groups, and hydration of epoxides was presented in Chapt. 10. Yet, despite the large variety of reactions and moieties examined in the previous chapters, many reactions remain that do not fit the categories already discussed. 

Hydration of epoxides.1 Nafion-H can serve as a catalyst for hydration or methanolysis of epoxides. 

Hydration of epoxides derived from long-chain uns turated Hk or oBters has been studied very extensively in a number of la hot a-tories. 2- s3°- 1 aa-l 77-WBS-18ef > w- Acid-catalyzed hydration ul r and trans- l,3-epoxyoctadecanoic acid, cm- and towtM-flj-epoxyrn ta-decanoic acid, cis- and, 10-epoxyoctadecanoic acid, and < - a-ul... 

Further investigations of the reaction suggest that the bidentate complex (154) is the reactive species which undergoes external attack by water or other nucleophiles present in solution. The enzymic hydration of epoxides and the possible role of metal ions has been discussed 501 the results obtained suggest that a metal ion is not involved at the active site of epoxide hydrase. 

Hydration of epoxides catalyzed by epoxide hydrolase is involved in both detoxication and intoxication reactions. With high concentrations of styrene oxide as a substrate, the relative activity of hepatic microsomal epoxide hydrolase in several animal species is rhesus monkey > human = guinea pig > rabbit > rat > mouse. With some substrates, such as epoxidized lipids, the cytosolic hydrolase may be much more important than the microsomal enzyme. 

Formation of a dihydrodiol by hydration of epoxide groups can be an important detoxication process in that the product is often much less reactive to potential receptors than is the epoxide. However, this is not invariably the case because some dihydrodiols may undergo further epoxidation to form even more reactive metabolites. As shown in Figure 7.3, this can happen with benzo(a)pyrene 7,8-epoxide, which becomes oxidized to carcinogenic benzo(a)pyrene 7,8-diol-9,10-epoxide. The parent polycyclic aromatic hydrocarbon benzo(a)pyrene is classified as a procarcinogen, or precarcinogen, in that metabolic action is required to convert it to a species, in this case benzo(a)pyrene 7,8-diol-9,10-epoxide, which is carcinogenic as such. 

Although most phase I reactions are oxidations, reductions, or hydrolyses, the hydration of epoxides and dehydrohalogenations also occur. A summary of the most important reactions is shown in Table 10.1. 

Stereochemical studies have shown that the hydration of epoxides (of cyclic olefins as well as arenes) is performed by epoxide hydrolase in such a way that irans-diols are formed. Aliphatic epoxides have also been shown to undergo frans-hydration, which means that frons-epoxides yield erythm-glycols and ds-epoxides result in f/jreo-glycols (Hammock et al., 1980). 

The hydration of epoxides [Eq. (26)] can be viewed as a special form of hydrolysis in which the elements of water are added to the epoxide without the resultant formation of more than one product, such as occurs in most hydrolytic reactions. This reaction is catalyzed by epoxide hydrolase. 

The polycyclic aromatic hydrocarbons (PAH) are common environmental pollutants that have been implicated as etiological factors in human chemical carcinogenesis (13, 14). One such PAH that has been studied extensively is benzo[a]-pyrene (G3). The metabolic activation of this compound to various reactive intermediates, including epoxides, phenols, and quinones, is performed by the cytochrome-P450-containing mixed function oxidase (MFO) system. Subsequent metabolic steps may involve the hydration of epoxides to dihydrodiols, mediated... 

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. 

Experiments with rat liver homogenates and microsomes have provided most of the data on the products of DMBA metabolism. The initial steps in DMBA metabolism are epoxide formation and hydroxylation of each methyl group 49, 257, 426, 502). Evidence has also been presented for enzymatic formation of a transannular peroxide however, this product is also formed nonenzymatically 69). The formation of the 5,6-epoxide of DMBA was demonstrated by crystallization of the radioactive metabolite to constant specific activity, by conversion to a glutathione conjugate, and by hydration to the 5,6-dihydrodiol (257). The other DMBA dihydrodiols presumably result from hydration of epoxides they were not observed in the presence of the epoxide hydrase initiator TCPO 502), The 8,9-dihydrodiol is the major dihydrodiol metabolite of DMBA formed in rat liver. 

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