Important liver molecule discovered - Brief Article

Nutrition Health Review, Fall, 2002

Chemists at the University of North Carolina at Chapel Hill have succeeded in determining the structure of a key molecule in the liver responsible for metabolizing more than 60 percent of drugs taken by humans.

The molecule, known as PXR, is the master regulator of a protein called cytochrome P450-3A, or CYP3A, which breaks down medications, scientists say. Like an electric switch, PXR turns on and off the machinery that metabolizes more than half of all drugs used and, for that reason, is critically important to human health.

Interactions involving the regulator molecule, scientifically known as a nuclear receptor, have led to so-called "St. John's wort babies" after the unregulated herbal antidepressant caused the molecule to render oral contraceptives ineffective, university chemists say. Similar interactions have caused certain powerful drugs used for acquired immunodeficiency syndrome (AIDS) and for organ transplantation to become less effective.

"This work is likely to become important clinically because drug companies have been clamoring to know how the human body recognizes their drugs and marks them for degradation," said Dr. Matthew R. Redinbo, lead author, Assistant Professor of chemistry at the university, and a member of the Lineberger Comprehensive Cancer Center. "Our work provides the first close glimpse into how that is accomplished."

The drug-drug interaction caused by PXR in humans may also be dangerous, he said.

"Imagine you are taking oral contraceptives and at the same time the herb St. John's wort," he says. "It's known that a constituent of St. John's wort, hyperforin, binds to PXR and turns on CYP3A4, which then breaks down lots of compounds in the liver, including contraceptives.

"More deadly examples of interactions mediated by PXR have also been described, including breakdown of the immunosuppressant cyclosporin and the anti-HIV drug Indinavir. Using the crystal structure of PXR, we may be able to predict these effects and possibly prevent such drug-drug interactions."

Most interactions in biology are highly specific, in that one chemical binds with high selectivity to a particular molecule or receptor, Dr. Redinbo said.

"These results will further help us to identify and prevent dangerous drug-drug interactions in humans and to understand how drugs are metabolized and disposed of."