Lee Study: Boosting P450 Enzyme Lowers Blood Pressure

Divisions Faculty Pharmacotherapy and Experimental Therapeutics Research,

Grayson Mendenhall
June 8, 2010

Scientists at the UNC Eshelman School of Pharmacy at the University of North Carolina at Chapel Hill have discovered that increasing levels of a certain enzyme in blood vessels can lower blood pressure, at least in mice, which could bode well for a new class of drugs currently in phase II clinical trials.

Investigators Craig Lee, PharmD, PhD, and Darryl Zeldin, MD, demonstrated that high levels of the enzyme cytochrome P450 cause mice to produce more of a substance called epoxyeicosatrienoic acid, or EET, which relaxes blood vessels and lowered blood pressure by 40 percent in the test groups. Their findings, “Endothelial Expression Of Human Cytochrome P450 Epoxygenases Lowers Blood Pressure And Attenuates Hypertension-Induced Renal Injury In Mice,” have been published online in the FASEB Journal of the Federation of American Societies for Experimental Biology. A new class of blood-pressure drugs called soluble epoxide inhibitors, or sEH, that increase EETs are undergoing human trials.

“This study adds to our understanding of the P450-EET pathway and its role in lowering blood pressure,” Lee says. “Prior studies have shown that manipulating EET levels, particularly in kidney cells, affects blood pressure. What’s novel about our approach is that we were able to lower blood pressure by increasing EET levels in the endothelial cells that line blood vessels. It is my hope that this new information will lead to new and better treatments for hypertension and other conditions affected by blood vessel function.”

Lee used a novel mouse model in this study that he created while working as a graduate student with Zeldin at the National Institute of Environmental Health Sciences. These mice have been genetically modified to produce large amounts of certain human versions of the P450 enzyme, specifically CYP2J2 and CYP2C8. When exposed to substances that raise blood pressure, the P450 mice had lower blood pressure and less damage to their kidneys than did a normal group of mice. High blood pressure can harm the kidneys and is a leading cause of kidney failure.

While this study focused on hypertension, Lee says his primary interest in the P450 pathway is in exploring how its role in regulating blood vessel function affects inflammation.

“Vascular inflammation is a key process in the development and progression of cardiovascular disease,” Lee says. “Studies in these mice will further our understanding of the role of the P450-EET pathway in this process, and help determine if increasing EETs may be a new and effective way to slow the inflammatory process in blood vessels. This could lead to new treatment strategies for patients with cardiovascular disease.”

Lee is an assistant professor in the Division of Pharmacotherapy and Experimental Therapeutics. Zeldin is an adjunct professor in the Division of Pharmacotherapy and Experimental Therapeutics and acting clinical director of the NIEHS Division of Intramural Research.

The other coauthors of the paper are Matthew L. Edin, Julie Foley, Laura M. DeGraff, J. Alyce Bradbury, Joan P. Graves, Fred B. Lih, James Clark, Page Myers, A. Ligon Perrow, and Kenneth B. Tomer of the Division of Intramural Research, National Institute of Environmental Health Sciences; Alison Kannon of the Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy; John D. Imig and Adrienne N. Lepp of the Department of Physiology, Medical College of Wisconsin; Oline K. Ronnekleiv and Nabil J. Alkayed of the Department of Physiology and Pharmacology and Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University; and John R. Falck. Department of Biochemistry, University of Texas Southwestern Medical Center.