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ShareJune 19, 2001 — CHAPEL HILL - Chemists at the University of North Carolina at Chapel Hill and GlaxoSmithKline 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, that breaks the medications down, scientists say. In other words, 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, the UNC chemists say. Similar interactions have caused certain powerful AIDS drugs and transplant drugs 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, assistant professor of chemistry at UNC and a member of the Lineberger Comprehensive Cancer Center. "Our work provides the first close glimpse into how that is accomplished."
Also, the drug-drug interaction PXR causes in humans can be dangerous, Redinbo said. "Imagine you are taking oral contraceptives and at the same time the herb St. John's wort," he said. "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 immunosupressant 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."
A paper on the subject will be published online by the journal Science, as part of the Science Express Web site, on June 14 (http://www.scienceexpress.org). Besides Redinbo, authors include UNC doctoral student Ryan E. Watkins and Dr. Steven A. Kliewer, a GlaxoSmithKline scientist. Most interactions in biology are highly specific in that one chemical binds with high selectivity to a particular molecule or receptor, Redinbo said.
"In contrast, PXR is highly promiscuous, meaning that it binds to dozens of well-known drugs and toxins, including the antibiotic rifampicin, the anti-cancer drug taxol and the controversial abortion pill RU-486," he said. "These compounds vary in size and shape, but PXR can handle them all."
Diffraction and biochemical studies the team conducted revealed that the crystal structure of PXR -- both alone and in combination with the cholesterol-lowering drug SR12813 -- contains a large, smooth pocket apparently able to accommodate this large variety of compounds. The cholesterol-lowering drug SR12813, for example, can fit into the PXR molecule in at least three different ways.
While PXR is chemically "promiscuous," it also is oddly specific, the UNC scientist said. Other groups have shown that while human PXR binds to many compounds that threaten humans, the mouse version of the molecule binds to a different set of chemicals that threaten mice.
"The fact that these differences exist probably reflects the different chemical challenges faced by mice and men during evolution," Redinbo said. "We have shown using our crystal structure and other studies that only a few chemical groups in PXR are responsible for this selectivity. By changing only four amino acids in mouse PXR to the corresponding residues in human PXR, we were able to 'humanize' the mouse PXR receptor in its response to specific chemicals.
"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."
Other authors of the Science paper are G. Bruce Wisely, Linda B. Moore, Dr. John L. Collins, Dr. Millard H. Lambert, Dr. Shawn P. Williams and Dr. Timothy M. Willson, all of GlaxoSmithKline in Research Triangle Park, N.C.
The research was supported by a Glaxo-UNC Collaborative Research Grant, the UNC Lineberger Comprehensive Cancer Center and a Burroughs Wellcome Career Award in the Biomedical Sciences to Redinbo.
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