The role of epoxide hydrolases in health and disease

Abstract

Epoxide hydrolases (EH) are ubiquitously expressed in all living organisms and in almost all organs and tissues. They are mainly subdivided into microsomal and soluble EH and catalyze the hydration of epoxides, three-membered-cyclic ethers, to their corresponding dihydrodiols. Owning to the high chemical reactivity of xenobiotic epoxides, microsomal EH is considered protective enzyme against mutagenic and carcinogenic initiation. Nevertheless, several endogenously produced epoxides of fatty acids function as important regulatory mediators. By mediating the formation of cytotoxic dihydrodiol fatty acids on the expense of cytoprotective epoxides of fatty acids, soluble EH is considered to have cytotoxic activity. Indeed, the attenuation of microsomal EH, achieved by chemical inhibitors or preexists due to specific genetic polymorphisms, is linked to the aggravation of the toxicity of xenobiotics, as well as the risk of cancer and inflammatory diseases, whereas soluble EH inhibition has been emerged as a promising intervention against several diseases, most importantly cardiovascular, lung and metabolic diseases. However, there is reportedly a significant overlap in substrate selectivity between microsomal and soluble EH. In addition, microsomal and soluble EH were found to have the same catalytic triad and identical molecular mechanism. Consequently, the physiological functions of microsomal and soluble EH are also overlapped. Thus, studying the biological effects of microsomal or soluble EH alterations needs to include the effects on both the metabolism of reactive metabolites, as well as epoxides of fatty acids. This review focuses on the multifaceted role of EH in the metabolism of xenobiotic and endogenous epoxides and the impact of EH modulations.

Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

“…Among these EHs, sEH and mEH have been extensively characterized because of their potential clinical value and the involvement of mEH in the metabolism of xenobiotics (detoxification of cytotoxic, mutagenic, and carcinogenic intermediates) (Morisseau and Hammock, 2005;ElSherbeni and El-Kadi, 2014;Kodani and Hammock, 2015;Václavíková et al, 2015). The mEH is the key hepatic enzyme that catalyzes the hydration of numerous xenobiotics such as the epoxides of 1,3-butadiene, styrene, naphthalene, benzo(a)pyrene, phenantoin, and carbamazepine (El-Sherbeni and El-Kadi, 2014;Rosa et al, 2016). The sEH, on the other hand, appears to have a rather restricted substrate selectivity being involved in the metabolism of endogenous epoxides and has not been shown to hydrate any toxic or mutagenic xenobiotics (Morisseau and Hammock, 2013).…”

Microsomal epoxide hydrolase 1 (EPHX1): Gene, structure, function, and role in human disease

“…While it detoxifies certain carcinogenic compounds, e.g., butadiene, benzene, styrene, etc. (Decker et al 2009), it can also activate procarcinogens such as polycyclic aromatic hydrocarbons on the other hand (Shou et al 1996, Casson et al 2006, El-Sherbeni and El-Kadi 2014). …”

Discovery and characterization of thermophilic limonene‐1,2‐epoxide hydrolases from hot spring metagenomic libraries

“…in the detoxification of reactive xenobiotics or endogenous metabolites and in the formation of biologically active mediators. The mammalian EHs, such as microsomal epoxide hydrolases (mEHs, EC 3.3.2.9) and soluble epoxide hydrolases (sEHs, EC 3.3.2.10), are widely studied in order to gain an understanding of their function in regulatory processes and disease [3].…”