Epoxide Hydrolases

Abstract

Epoxides are three‐membered carbon–oxygen compounds that typically arise from the metabolism of endogenous and xenobiotic compounds via chemical and enzymatic oxidation processes. Many different oxygenase enzymes are capable of forming epoxide derivates, from either arene or alkene substrate; however, the cytochrome P450 monooxygenases are principal contributors to their generation. Certain epoxides are highly electrophilic and chemically reactive, and they have been implicated as initiators of various cellular toxicities, including the formation of DNA mutations and ultimately, cancers. Therefore, it is of vital importance for the organism to regulate levels of these reactive species. A single mammalian enzyme, microsomal epoxide hydrolase (EPHX1, mEH), functions as a predominant pathway responsible for detoxification of xenobiotic epoxides, as well as bioactivation pathway for certain xenobiotic epoxides. In contrast, another important epoxide hydrolase, soluble epoxide hydrolase (EPHX2, sEH), has more recently been established as a mediator of epoxide hydrolysis of several endogenously derived epoxyeicosatrienoic acids (EETs), intermediates resulting from arachidonic acid metabolism. In this respect, EPHX2 is now characterized as an important regulator of physiological processes, such as blood pressure and inflammation, and has emerged as a promising therapeutic target for pharmacological intervention. This chapter reviews the biochemistry, biological regulation, genetics, and pharmacological relevance of these important enzyme systems.