Superfund Research Program
Potent Inhibitors are Discovered for Soluble Epoxide Hydrolases, Enzymes That Have an Important Role in the Metabolism of Environmental Contaminants
Epoxide hydrolases are enzymes that catalyze the opening of epoxide rings by addition of a water molecule. Found in a variety of organisms - mammals, insects and plants to name a few - these enzymes are necessary for processing the wide range of epoxide-containing compounds to which humans are exposed. For instance, epoxides form inside the body during the metabolism of drugs and environmental contaminants, are produced in nature by molds and other organisms, and are used extensively in industry. Some examples of the compounds processed by epoxide hydrolases include benzene oxide, a human metabolite of benzene, and the fatty acid epoxides that are common in foods. Although epoxide hydrolases catalyze the same reaction for each different substrate, these enzymes appear to play a dual, contradictory role in the human body.
On the one hand, epoxide hydrolases are critical to the body's defense against many toxic substances found in the environment. They are involved in metabolic pathways that transform a wide range of lipophilic chemicals to compounds with increased water solubility, which expedites the clearance of the parent compound from the body and reduces the chances of toxic effects. Some of the substrates for epoxide hydrolases are potent mutagens, toxins and carcinogens; thus, these enzymes offer significant protection against cellular injury.
However, epoxide hydrolases are also associated with adverse effects in the body. They participate in the biosynthesis of molecules that have been associated with multiple organ failure and acute respiratory distress syndrome in humans. They also play a role in activating certain environmental contaminants to highly reactive compounds that bind to DNA and other macromolecules, events that can lead to mutations and cellular injury. It is important to gain a better understanding of these enzymes, considering their paradoxical nature.
Researchers at the University of California-Davis (UC-Davis) recently discovered new inhibitors of soluble epoxide hydrolases (sEH), the form of the enzyme that exists in the cell cytosol. Previously described sEH inhibitors are relatively unstable and work only transiently. These new inhibitors - specific urea and carbamate compounds - are highly potent and stable, representing a significant advance in the development of sEH inhibitors.
The discovery of these inhibitors has already proven useful for acquiring new insight into sEH. Inhibitors are commonly used to determine the location of an enzyme's active site and to study factors that control enzyme activity. In a recent collaborative study with scientists at the University of Pennsylvania, one of the dialkylurea inhibitors was used to locate the active site of sEH and to investigate the enzyme's mechanism of action, two aspects of sEH that previously were not well described.
These inhibitors also have potential pharmacological uses. Many commonly used therapeutic agents work by inhibiting a target enzyme that is involved in a metabolic process which contributes to toxicity or illness. Recognizing this, the UC-Davis researchers investigated whether one of the more powerful inhibitors, N,N'-dicyclohexylurea (DCU), could reduce the toxicity of epoxy-linoleate. Epoxy-linoleate is an epoxide derivative of linoleic acid (a fatty acid) that has been associated with acute respiratory distress syndrome in humans. It is activated to its toxic form by sEH.
Cultured cells pretreated with DCU were protected from the toxic effects normally observed after exposure to epoxy-linoleate. Moreover, DCU prolonged the life of mice exposed to epoxy-linoleate, demonstrating its ability to block the activity of sEH in vivo. These results show that DCU and potentially some of the other new inhibitors may be powerful tools for investigating sEH as a pharmacological target, particularly for treating the symptoms of acute respiratory distress syndrome and other conditions that are exacerbated by the activity of sEH.
But the discovery of these potent inhibitors also highlights a potential environmental and public health concern. Certain alkylurea pesticides and herbicides contain pharmacophores (chemicals that have the minimum set of features necessary for interaction with an active site) similar to the sEH inhibitors that were investigated in these studies. Thus, these pesticides and herbicides could affect our ability to detoxify environmental contaminants and metabolize the numerous epoxide-containing compounds to which we are exposed.
As these studies have shown, these new sEH inhibitors have immense practical value, already contributing to a more sophisticated understanding of soluble epoxide hydrolases. With their powerful ability to block epoxide metabolism both in vitro and in vivo, these inhibitors promise to be useful in the future as well, not only for exploring the role of epoxides and their metabolites in toxicity and human illness, but also for developing new pharmaceutical agents. However, this discovery also serves as a warning: inadvertent exposure to the pesticides and herbicides that are structurally related to these inhibitors may pose a health risk by diminishing our ability to process mutagenic and carcinogenic epoxides.
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To learn more about this research, please refer to the following sources:
- Argiriadi MA, Morisseau C, Hammock BD, Christianson DW. 1999. Detoxification of environmental mutagens and carcinogens: Structure, mechanism, and evolution of liver epoxide hydrolase. Proc Natl Acad Sci U S A 96:10637-10642. PMID:10485878
- Morisseau C, Goodrow MH, Dowdy DL, Zheng J, Greene JF, Sanborn JR, Hammock BD. 1999. Potent urea and carbamate inhibitors of soluble epoxide hydrolases. Proc Natl Acad Sci U S A 96(16):8849-8854. PMID:10430859
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