Mammalian epoxide hydrolases in xenobiotic metabolism and signalling

Abstract

Epoxide hydrolases catalyse the hydrolysis of electrophilic-and therefore potentially genotoxic-epoxides to the corresponding less reactive vicinal diols, which explains the classiWcation of epoxide hydrolases as typical detoxifying enzymes. The best example is mammalian microsomal epoxide hydrolase (mEH)-an enzyme prone to detoxiWcation-due to a high expression level in the liver, a broad substrate selectivity, as well as inducibility by foreign compounds. The mEH is capable of inactivating a large number of structurally diVerent, highly reactive epoxides and hence is an important part of the enzymatic defence of our organism against adverse eVects of foreign compounds. Furthermore, evidence is accumulating that mammalian epoxide hydrolases play physiological roles other than detoxiWcation, particularly through involvement in signalling processes. This certainly holds true for soluble epoxide hydrolase (sEH) whose main function seems to be the turnover of lipid derived epoxides, which are signalling lipids with diverse functions in regulatory processes, such as control of blood pressure, inXammatory processes, cell proliferation and nociception. In recent years, the sEH has attracted attention as a promising target for pharmacological inhibition to treat hypertension and possibly other diseases. Recently, new hitherto uncharacterised epoxide hydrolases could be identiWed in mammals by genome analysis. The expression pattern and substrate selectivity of these new epoxide hydrolases suggests their participation in signalling processes rather than a role in detoxiWcation. Taken together, epoxide hydrolases (1) play a central role in the detoxiWcation of genotoxic epoxides and (2) have an important function in the regulation of physiological processes by the control of signalling molecules with an epoxide structure.

Microsomal epoxide hydrolase polymorphisms

“…In recent years, sEH has attracted attention due to its role in the turnover of lipid derived epoxides, which are signaling lipids with functions in regulatory processes such as the control of blood pressure, inflammatory processes and cell proliferation. Furthermore, sEH is thought to be a promising target for pharmacological inhibition to treat hypertension and possibly other diseases (3). mEH classically plays a major role in xenobiotic metabolism and has been described as a biotransformation enzyme.…”

“…It has been reported that the mammalian microsomal epoxide hydrolase (meH) plays a key role in xenobiotic metabolism. The main function of mEH is the breakdown of genotoxic and carcinogenic epoxides to less harmful metabolites and the protection of macromolecules from the electrophilic attack of reactive intermediates (3). However, in the case of some polycyclic aromatic hydrocarbons, such as benzo(a)pyrene, present in tobacco smoke, dihydrodiol formation stabilizes bay-region epoxides, increasing the mutagenic and carcinogenic potential of the product (4,5).…”

Increased cancer burden among pesticide applicators and others due to pesticide exposure

“…101 One xenobiotic metabolizing enzymes identified with a variant allele linked to petroleum oil herbicide exposure and a higher prostate cancer risk was found in the gene that encodes microsomal epoxide hydrolase, which is an important detoxication enzyme of reactive epoxides. 27 Epoxides are chemicals that are formed via cytochrome P450-mediated monooxygenation of carcinogens, such as benzo(a)pyrene found in cigarette smoke and aflatoxin B1, which is produced by the mold Aspergillus flavus. Epoxides produced in vivo are often chemically unstable and can covalently modify DNA, thus forming DNA adducts with a propensity to cause mutation.…”

Lipoxygenase-catalyzed transformation of epoxy fatty acids to hydroxy-endoperoxides: a potential P450 and lipoxygenase interaction

“…Nonetheless, in biological systems opening of the epoxide ring is likely to occur on exposure to peroxidases, in which case the products will be fatty acid triols. The same triols could arise also from hydrolysis of the precursor hydroperoxy-epoxides, which are likely substrates for epoxide hydrolase ( 35 ).…”