Molecular properties and biological functions of microsomal epoxide hydrase.

Abstract

Many drugs, mutagens, and environmental carcinogens are aromatic or olefinic compounds and are metabolized in mammals by enzymes localized in the endoplasmic reticulum of various tissues (1, 2). Biologically active arene oxides which are formed by the microsomal cytochrome P-450containing monooxygenase system are the initial products from many of these compounds, polycyclic aromatic hydrocarbons being one class that has been extensively investigated (3-7). These reactive epoxides and arene oxides can be hydrated enzymatically via microsomal epoxide hydrase (epoxide hydratase, Ee 4.2.1.63) to chemically less reactive trans-dihy­ drodiols. In addition, arene oxides can undergo nonenzymatic isomeriza­ tion to phenols, be conjugated with glutathione via the enzyme glutathione-S-epoxide transferase, and also react with DNA, RNA, and proteins to form covalently bound products. Since certain of these arene oxides have toxic, mutagenic, and carcinogenic properties, the ability of epoxide hydrase to convert epoxides to dihydrodiols has been recognized as an important metabolic step in the detoxification of .these compounds. However, most recent investigations (8-16) have also '!fuown that the cyto­ chrome P-450 system and epoxide hydrase convert many polycyclic aro­ matic hydrocarbons to more reactive bay region diol epoxide derivatives. Thus, epoxide hydrase plays a central role in both the inactivation of mutagenic and carcinogenic metabolites of polycyclic aromatic hydrocar-