Scientists have discovered the structure of a molecule responsible for metabolizing more than half of all drugs, according to the results of a new study. The findings, published online by the journal Science, will help drug manufacturers to better understand how drugs are broken down and disposed of, and should aid in preventing dangerous cross-reactions between drugs.
This key molecule, dubbed PXR, controls a protein known as cytochrome P450-3A (abbreviated to CYP3A) that breaks down medications. It does this by binding to the compounds, thereby tagging them for degradation. But in contrast to most biological interactions, in which a molecule or receptor binds to a single chemical, University of North Carolina chemist Matthew R. Redinbo notes, PXR is "highly promiscuous," binding to compounds ranging from the anti-cancer drug Taxol to the abortion pill RU-486. If someone is taking more than one drug, this can lead to problems. "Imagine you are taking oral contraceptives and at the same time the herb St. John's wort," Redinbo 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." Other negative interactions mediated by PXR, he adds, can lead to breakdown of the immunosuppressant cyclosporin and the anti-HIV drug Indinavir. The new work provides welcome insight into the mediating molecule. "Using the crystal structure of PXR," Redinbo remarks, "we may be able to predict these effects and prevent such drug-drug interactions."