Environmental Factor, November 2006, National Institute of Environmental Health Sciences
Distinguished Lecturer Outlines Hypertension Breakthrough
By Eddy Ball
On October 10 in Rodbell Auditorium, University of California at Davis Distinguished Professor Bruce Hammock, Ph.D., delivered the second talk in the Distinguished Lecture series. In a lecture titled "Herbicides to Hypertension: The Soluble Epoxide Hydrolase [sEH] as a Therapeutic Target for Hypertension, Inflammation and Analgesia," Hammock summarized a discovery process that he described as "circuitous and serendipitous," leading to the development of what could be the next generation of treatment for hypertension and inflammation in humans.
Hosted by William Suk, Ph.D., the lecture took an audience of NIEHS and local area scientists from Hammock's basic scientific research sponsored by a Superfund grant into insect control and xenobiotic metabolism to anticipated applications of sEH inhibitors in human health that may soon enter Phase Ia/Ib clinical trials. "I hope I can entertain you," Hammock told his audience at the start of the lecture, "with a nice story that goes from two aspects of very fundamental science towards something I think is getting very, very close to potentially helping patients."
With the NIEHS grant he received in 1973, Hammock began to study epoxide hydrolases (EH), enzymes that degrade xenobiotics and help keep people alive by rendering epoxides in pesticides and combustion byproducts less harmful. The early research discovered two forms of EH, microsomal and soluble, and the possibility that the soluble form might have a biological role. Hammock performed his early research on mice, which have high levels of sEH, rather than rats, which have very low concentrations of the enzyme. Because of its role in detoxification, Hammock and his colleagues found sEH in the liver, but they also discovered an unexpected distribution pattern of sEH outside the liver. High concentrations of the enzyme were found in the vascular endothelium, where sEH impacted vasodilation and inflammation.
By manipulating the transitional stage of sEH metabolism, Hammock soon discovered that preserving fatty acids in epoxide form could influence the course of the arachidonic acid cascade, shifting it from the production of inflammatory compounds to the production of anti-inflammatory compounds. He discovered that sEH inhibitors improved an organism's response to endoxins, such as lipopolysaccharides, by helping to maintain blood pressure at normal levels, enhancing airway response by down-regulating inflammation and acting to reduce pain perception. In a series of recent studies, Hammock and colleagues, including NIEHS Senior Investigator Darryl Zeldin, have demonstrated the therapeutic benefits of sEH inhibition and explored the synergistic effects of sEH inhibitors in combination with COX inhibitors. They also have identified one genetic polymorphism, K55R, that is associated with higher levels of sEH in affected individuals.
Over the course of his lecture, Hammock acknowledged the importance of NIEHS grants in his discovery process. "The work has been funded probably 10 percent by the Department of Agriculture and 90 percent by NIEHS," he explained. However, now Hammock faces the drug-development "valley of death," the funding gulf that stretches from government-sponsored pre-clinical research with laboratory animals to the initiation of human clinical trials funded by pharmaceutical manufacturers and venture capitalists.
An author of more than 625 peer-reviewed articles, Hammock is a leader in his fields of research. He was elected to the National Academy of Sciences in 1999 and has received a long list of awards and recognitions for his achievements. He has received the Frasch and Spencer Awards of the American Chemical Society and the Alexander von Humboldt Award, one of the most prestigious in the field of agriculture. If Hammock's work with sEH inhibition lives up to its promise of what he called "the first new target for anti-hypertension in twenty years," his work may emerge as a major contribution to the prevention of hypertension and its pathological effects throughout the body.