Epoxide hydrolases are not only a molecular sponge sucking up genotoxic epoxides: new roles in control of blood pressure, inflammation as well as nociception and cell proliferation

Abstract

Recently, the Archives of Toxicology have started a series of review articles about xenobiotic metabolizing enzymes, systematically addressing nomenclature and gene evolution, catalytic mechanisms, toxicological relevance, and polymorphisms (Bolt and Hengstler 2008). Olavi Pelkonen has already reviewed cytochrome P450 enzymes (Pelkonen et al. 2008) and CP Strassburg and TO Lankisch have contributed comprehensive articles about UDP-glucuronosyltransferases (Strassburg et al. 2008; Lankisch et al. 2008). We are happy that Michael Arand, Annette Cronin and Martina Decker from the University of Zurich continued our series of review articles about drug-metabolizing enzymes with an excellent contribution about mammalian epoxide hydrolases (Decker et al. 2009, this issue). Traditionally, epoxide hydrolases are known as primarily detoxifying enzymes that catalyze the hydrolysis of epoxides (Hengstler et al. 1998). Importantly, epoxide hydrolases act by a two-step reaction, which has some important implications. In a Wrst step, two tyrosines in the catalytic center of the enzyme bind the epoxide by hydrogen bonding to the ring oxygen, and an aspartic acid residue attacks a carbon atom of the oxirane ring (Oesch et al. 2000, 2001). Simultaneously, the bond of this carbon is released and an ester intermediate is formed. In a second step, the covalent intermediate is hydrolyzed and the detoxiWed product of the epoxide hydrolase reaction is released. Importantly, the formation of the ester intermediate (step 1) proceeds by three orders of magnitudes faster than the subsequent hydrolysis (step 2). Therefore, epoxide hydrolases may act like a molecular sponge that binds and inactivates dangerous epoxides rapidly, whereas the subsequent release of the product occurs only slowly (Oesch et al. 2001). This explains why epoxide hydrolases can keep tissue concentrations of free epoxides very low up to concentrations of epoxides where the epoxide hydrolases are titrated out leading to a sudden burst of the epoxides. This sponge eVect contributes to threshold mechanisms observed for some genotoxic epoxides (Oesch et al. 2001; Hengstler et al. 2003, 1997). However, in their current review Decker et al. (2009) show that mammalian epoxide hydrolases are more than just a sponge for genotoxic waste. The authors collected convincing evidence that epoxide hydrolases are also involved in control of the following functions: