chapter  12
41 Pages

Epoxide hydrolases

The epoxide hydrolases are a group of catalytically-related enzymes, each with its own unique structural and biochemical characteristics. Because they are related but distinct enzymes, the problem of nomenclature is somewhat difficult. Early descriptions of enzymic epoxide hydrolysis named the enzyme involved ‘epoxide hydrolase’ (Maynert et al., 1970) or ‘epoxide hydrase’ (Jerina et al., 1968a). Other contemporary descriptions also used the term ‘epoxide hydratase’. In 1978, the Nomenclature Committee of the International Union of Biochemistry recommended that the enzyme be called ‘epoxide hydrolase’ (EC 3. 3.2.3). At that time it was not widely recognized that more than one epoxide hydrolase existed, and it was assumed that the enzymic hydrolysis of all epoxides was catalyzed by a single enzyme located in the endoplasmic reticulum, or perhaps by the same enzyme adventitiously present to a small degree in the cytosolic fraction. With the subsequent demonstration of a unique epoxide hydrolase located primarily in the cytosol and peroxisomes, which had distinctly different biochemical properties from those of the microsomal enzyme, the terms ‘microsomal epoxide hydrolase’ or ‘mEH’, and ‘cytosolic epoxide hydrolase’ or ‘cEH’, were informally adopted to differentiate the two distinct hydrolases. Further complications arose with the demonstration that mEH was found in cytosol and nuclei, and that cEH could be found in microsomes (see below). Furthermore, a second unique microsomal epoxide hydrolase, which hydrolyzes cholesterol 5, 6-oxides, and a second unique cytosolic epoxide hydrolase, which hydrolyzes leukotriene A4 have been discovered. The problem of nomenclature for these enzymes has yet to be resolved; suggestions include that they be differentiated by subcellular location, by substrate specificity, or simply by unique numbers. Due to the lack of completely rigorous subcellular localization or substrate specificity, the use of a system of unique numbers or letters for each epoxide hydrolase, as is now the accepted system for cytochrome P-450 nomenclature, appears to be the most systematic. However in the case of this review, the following definitions will be subsequently used: ‘Microsomal epoxide hydrolase’ or ‘mEH’ will be used to describe the form of epoxide hydrolase that is found predominantly in the endoplasmic reticulum and that catalyzes the hydrolysis of a broad spectrum of xenobiotic epoxides, specifically including arene oxides. This enzyme has also been referred to as ‘mEHb’ (Oesch et al., 1984), ‘EH1’ (Guenthner and Oesch, 1983) and ‘mCSO’ (Finley and Hammock, 1988). ‘Cytosolic epoxide hydrolase’ or ‘cEH’ will be used to describe that form of epoxide hydrolase that is primarily found in cytosol and

peroxisomes and that specifically catalyzes the hydrolysis of trans-substituted styrene oxides. This enzyme has also been referred to as ‘EH2’ (Guenthner and Oesch, 1983) and ‘cTSO’ (Finley and Hammock, 1988). ‘Cholesterol 5, 6-oxide hydrolase’, or ‘ChEH’ will be used to describe that epoxide hydrolase that specifically catalyzes the hydrolysis of cholesterol 5, 6α-and 5, 6β-oxides. This enzyme has also been referred to as ‘mEHch’ (Oesch et al., 1984) and ‘mCE’ (Finley and Hammock, 1988). Finally, ‘LTA4 hydrolase’ or ‘LTA4H’, will be used to define that epoxide hydrolase that stereo-selectively converts leukotriene A4 to leukotriene B4.