Receptor that Protects Mice from Toxic Overload May Hold a Key to Cholesterol-Related Illnesses in Humans

City of Hope
Tuesday, 4 February 2003

Research published today in Proceedings of the National Academy of Sciences suggests that a receptor in the cells of mice that protects them from toxins may hold a key to understanding and treating cholesterol-related illnesses in humans.

Pregnane X receptor, or PXR, is present in humans but does not recognize or eliminate all toxins as effectively as it does in our diminutive counterparts. In mice, PXR senses the presence of excess cholesterol by-products and immediately activates special pathways that remove these toxins.

"PXR essentially acts like a sophisticated biological smoke detector. It knows when there is smoke and calls in the fire engines," says Barry Forman, M.D., Ph.D., associate professor, Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute and City of Hope Gonda Diabetes Center. "This important mechanism protects mice from the often severe effects suffered by patients with high levels of certain cholesterol by-products or metabolites."

The central problem in humans is that the PXR receptor is not activated by the metabolites to trigger an effective response and clear away the cholesterol.

The discovery came in a study of Cerebrotendinous Xanthomatosis, or CTX, a rare and often fatal disorder caused by excessive cholesterol metabolites. Less than 100 people in the United States suffer from CTX, but harnessing PXR could benefit not only those patients but also millions of people with high cholesterol worldwide. High cholesterol is a leading cause of heart disease, the number one cause of death in the U.S., and if strokes.

The research further suggests that CTX and other cholesterol-related illnesses could be treated or possibly even prevented with existing drugs that do activate the PXR receptor in humans. These drugs include rifampicin and St. John's Wort, an over-the-counter herbal agent. Future studies are needed to determine whether these drugs can remove cholesterol metabolites in CTX patients or in individuals with high cholesterol.

Co-investigators include Isabelle Dussault, Ph.D., Hye-Dong Yoo, Ph.D., Min Lin, M.S., Eric Wang; B.S. and Ming Fan, M.S., all of City of Hope; Ashok K. Batta, Ph.D. and Gerald Salen, M.D., both of New Jersey Medical School, Newark, and Veterans Affairs Medical Center, East Orange, N.J.; and Sandra K. Erickson, Ph.D., University of California and Veterans Affairs Medical Center, San Francisco.

For more information, or to contact City of Hope, see their website at: www.cityofhope.org