Gerry Brooks and epoxide hydrolases: four decades to a pharmaceutical

Abstract

The pioneering work of Gerry Brooks on cyclodiene insecticides led to the discovery of a class of enzymes known as epoxide hydrolases. The results from four decades of work confirm Brooks' first observations that the microsomal epoxide hydrolase is important in foreign compound metabolism. Brooks and associates went on to be the first to carry out a systematic study of the inhibition of this enzyme. A second role for this enzyme family was in the degradation of insect juvenile hormone (JH). JH epoxide hydrolases have now been cloned and expressed from several species, and there is interest in developing inhibitors for them. Interestingly, the distantly related mammalian soluble epoxide hydrolase has emerged as a promising pharmacological target for treating hypertension, inflammatory disease and pain. Tight-binding transition-state inhibitors were developed with good ADME (absorption, distribution, metabolism and excretion). These compounds stabilize endogenous epoxides of fatty acids, including arachidonic acid, which have profound therapeutic effects. Now EHs from microorganisms and plants are used in green chemistry. From his seminal work, Dr Brooks opened the field of epoxide hydrolase research in many directions including xenobiotic metabolism, insect physiology and human health, as well as asymmetric organic synthesis. 

EPHX1 polymorphisms do not modify esophageal carcinoma susceptibility in Dutch Caucasians

“…Microsomal EH hydrolizes the epoxides, generating water-soluble, less mutagenic, chemically less-active and excretable glycols. Conversely other hydrocarbons such as benzo(a)pyrene, are metabolized by mEH resulting in more carcinogenic diol epoxides with DNA alkylating abilities (8). This supports the concept that mEH, depending on the substrate, has carcinoprotective as well as toxicity-enhancing properties.…”

“…Although it is suggested that the EPHX1 gene is expressed in many mammalian tissues (5,8) including those of the aerodigestive tract (15,25), to our knowledge no data on EPHX1 mRNA expression in the cancerous esophagus is known. Consequently it is complicated to interpret the most recent results of Ihsan et al (15), since additionally the overall data report inconsistent findings regarding esophageal cancer risk.…”

“…The mEH locus is located on chromosome 1q42 and it is expressed in nearly all human tissues (8). In the EPHX1 gene, two frequent substitution polymorphisms are known; c.337T→C on exon 3 and c.416A→G on exon 4, respectively, resulting in the replacement of Tyrosine (Y) → Histidine (H) at codon 113 and Histidine (H) → Arginine (R) at codon 139 (9).…”

Naturally occurring monoepoxides of eicosapentaenoic acid and docosahexaenoic acid are bioactive antihyperalgesic lipids

“…In vivo, inhibition of sEH has been demonstrated to stabilize EETs and presumably other lipid epoxides to lead to diverse biological activities including antihyperalgesia, antihypertension, and anti-infl ammation in animal models. Inhibition of sEH is being considered as a potential therapeutic approach for hypertension, vascular infl ammation, and pain ( 10,13,26,27 ). Here, we tested the hypothesis that EpDPE and EpETE are substrates for sEH, and that they possess parallel biological activity with EET in reducing pain associated with infl ammation.…”

“…In murine brain, sEH is responsible for at least twothirds of the EET hydrolysis ( 41 ). Pharmacological inhibition of sEH has been demonstrated to stabilize EETs and is being considered as a potential therapeutic approach for hypertension, vascular infl ammation, and pain ( 10,13,26,27 ). Inhibition of sEH is benefi cial also in ischemic brain injury and stroke ( 42 ).…”