Epoxide hydrase

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 epoxidation of AFB has been associated with aldrin epoxidase (AE) activity in trout (30). As with other epoxide carcinogens, OAFB may be a substrate 7or epoxide metabolizing enzyme systems such as epoxide hydrase (EH) (EC4.2.1.63) and glutathione-S-epoxide transferase (GTr) (EC4.4.1.7) found in mammals and fish (31, 32, 33, 34). AFB also undergoes a variety of other reactions, generally to less toxic metabolites depending on the species of animal involved (35, 36). The primary AFB metabolite in rainbow trout has been shown to be a reduced form of AFB, aflatoxicol (AFL) (24). 

Figure 1. Epoxide hydrase and GSHt activities of trout hepatic microsomes and...

P. R. Ortiz de Montellano, A. S. Boparai, Aliphatic 3,4-Epoxyalcohols. Metabolism by Epoxide Hydrase and Mutagenic Activity , Biochim. Biophys. Acta 1978, 544, 504 - 513. 

P. M. Dansette, V. B. Makedonska, D. M. Jerina, Mechanism of Catalysis for the Hydration of Substituted Styrene Oxides by Hepatic Epoxide Hydrase , Arch. Biochem. Biophys. 1978, 187, 290 - 298. 

Epoxide hydrolases have also occasionally been termed epoxide hydratases or epoxide hydrases ... 

Oesch, F. (1973) Mammalian epoxide hydrases Inducible enzymes catalysing the inactivation of carcinogenic and cytotoxic metabolites derived from aromatic and olefinic compounds. Xenobiotica. 3, 305-340... 

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... 

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. 

The diol epoxides are generally formed by epoxidation of the trans-diols formed by the opening of the arene oxide by epoxide hydrase. A mechanism for phenanthrene is illustrated in Scheme 6 absolute stereochemistry is not implied.208... 

Parkki MG. 1981. Inhibition of rat hepatic microsomal epoxide hydrase by heavy- and organometals in vitro. Adv Exp Med Biol 136 729-738. Part A. 

In an attempt to identify the proposed epoxide intermediate of chlorobenzene, Oesch (1973) co-administered the epoxide hydrase inhibitor cyclohexane oxide together with chlorobenzene to rats. Instead of increasing the toxicity of chlorobenzene as expected, through the inhibition of epoxide hydrase, cyclohexane oxide actually decreased the metabolism of chlorobenzene and its necrotic toxicity on the liver, suggesting that the metabolism of chlorobenzene is partially responsible for its liver toxicity. 

Oesch F, Jerina DM, Daly JW, et al. 1973. Induction, activation and inhibition of epoxide hydrase An anomylous prevention of chlorobenzene - induced hepatotoxicity by an inhibitor of epoxide hydrase. Chem Biol Interact 6 189-202. 

The metabolism of PAH compounds is mentioned here with benzo(a)pyrene as an example. Several steps lead to the formation of the carcinogenic metabolite product of benzo(a)pyrene. After an initial oxidation to form the 7,8-epoxide, the 7,8-diol is produced through the action of epoxide hydrase enzyme, as shown by the following reaction ... 

Graham S. M. and Prestwich G. D. (1992) Tissue distribution and substrate specificity of an epoxide hydrase in the gypsy moth Lymantria dispar. Experentia 48, 19-21. 

Prestwich G. D., Graham S. M. and Konig W. A. (1989) Enantioselective opening of (+)-and (-)-disparlure by epoxide hydrase in gypsy moth antennae. J. Chem. Soc. Commun., 575-577. 

Figure 1. Metabolic pathways for activation of DMBA. MFO, mixed function oxidase EH, epoxide hydrase.

Identification of DNA-Reactive Metabolites Generated in a Target Tissue, Mouse Skin, In Vivo. Our initial studies focused on activation of DMBA in mouse embryo cells in culture because of the ease of isolation of sufficient DNA for adduct characterization. The cells were exposed to DMBA and the isolated DNA enzymatically hydrolyzed to deoxyribonucleosides. DMBA-deoxyribonucleoside adducts were characterized by fluorescence measurements (11,22), by photosensitivity studies (12) and by column chromatography (23,24). These studies provided evidence that the DNA-reactive metabolite generated in these cells is a bay region dihydrodiol epoxide. The enzymatic steps in this activation pathway (Figure 1) involve oxidation of DMBA by mixed function oxidases to a 3,4-epoxide which is converted by epoxide hydrase to a 3,4-dihydro-diol. This is, in turn, oxidized by mixed function oxidases to the dihydrodiol epoxide. 

Mukhtar, H., R.M. Philpot, and J.R. Bend. The postnatal development of microsomal epoxide hydrase, cytosolic glutathione S-transferase, and mitochondrial and microsomal cytochrome P-450 in adrenals and ovaries of female rats. Drug Metab. Dispos. 6 577-583, 1978. 

In the mid-1960s we showed firstly that the natural tolerance of houseflies to cyclodienes resulted mainly from oxidative detoxication (33 55) and secondly that another enzyme system, epoxide hydrase, converted certain dieldrin analogues into the corresponding trans-diols, (56,57) Interspecific differences in ability to attack enzymatically the unchlorinated ring systems of various analogues, either oxidatively and/or hydratively (if appropriate) can confer selective toxicity between insect species and also between insects and mammals (58) ... 

Epoxide rings of certain alkene and arene compounds are hydrated enzymatically by epoxide hydrolases to form the corresponding iram-dihydrodiols (Figure 10.11). The epoxide hydrolases are a family of enzymes known to exist both in the endoplasmic reticulum and in the cytosol. In earlier studies they were named epoxide hydratase, epoxide hydrase, or epoxide hydrolase. Epoxide hydrolase, however, has been recommended by the International Union of Biochemists Nomenclature Committee and is now in general use. 

Electrostatic isopotential (EIP) minima186 often identify sites and ease of metabolism by epoxide hydrase, an enzyme responsible for the conversion of epoxides to diols by the addition of water. Molecular electrostatic potential energy calculations also are probably the best means of identifying positions of epoxidation and, possibly, metabolism in general. In the case of aflatoxin B for example, EIP maxima and minima calculated by the CNDO/2 method all lie close to the known sites of metabolism and, in particular, the formation of the carcinogenic 2,3-epoxide is readily predicted.189... 

P. Politzer and P. R. Laurence, Carcinogenesis, 5, 845 (1984). Relationships between the Electrostatic Potential, Epoxide Hydrase Inhibition, and Carcinogenicity for Some Hydrocarbon and Halogenated Hydrocarbon Epoxides. 

Epoxide rings of alkene and arene compounds are hydrated to form trans-diols. The enzymes that catalyze the addition of a molecule of water to an epoxide ring to yield diols are called epoxide hydrolases (also known as epoxide hydrases). Epoxide hydrolase activity has been detected in numerous species of insects. Enzymatic epoxide hydration of certain cyclodiene insecticides and their analogs has been demonstrated in the housefly, blowfly (Calliphora erythrocephala), yellow mealworm (Tenebrio molitor), Madagascar cockroach (Gromphadorhina portentosa), southern army worm (Spodoptera eridania), and red flour beetle (Tribolium castaneum). Epoxide hydrolase is also important in the metabolism of juvenile... 

Because of its position as the first member of the (4n + 3) annulenone series", cyclopropenone (56) has been the subject of much interest The diphenyl derivative 14 was the st of the cyclopropenones to be isolated and because of its stability and ready availability it remains the most studied cyclopropenone Compound 14 is a strong contact sensitizer which causes allergies and brings out blisters on the skin, and it is also an in vitro stimulator of the activity of microsomal epoxide hydrase. Parent 56, reported in 1967, is stable for long periods below its melting point ( — 29 to —28 °C) when pure, but it polymerizes at higher temperatures organic solutions of 56 have moderate stability at ambient temperatures. 

Scheme 3, The metabolism and detoxification of drugs and environmental chemicals via the mixed function oxygenase, glutathione transferase, and epoxide hydrase pathways.

Table VII. Hepatic Epoxide Hydrase and Glutathione Transferase in Normal and Ascorbate Deficient Guinea Pigs...

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