Drugs clearing becomes crystal clear

The PXR molecule. Click on picture to get animation gif.

The structure of a key molecule that helps to clear drugs from cells has been determined by chemists at the University of North Carolina at Chapel Hill and GlaxoSmithKline. The molecule, PXR, is the master regulator of a protein called cytochrome P450-3A, or CYP3A, which is then responsible for breaking down more than 50% of the drugs used in medicine.

PXR is a highly promiscuous molecule binding to dozens of drugs and toxins, such as the antibiotic rifampicin, the anticancer drug paclitaxel (Taxol) and the abortion pill RU-486. The interactions between drugs and this regulatory molecule, a nuclear receptor, and certain drugs have led to

	Matthew Redinbo

complications. For instance, interference between the unregulated antidepressant herbal remedy St. John's wort and this receptor renders the female oral contraceptive ineffective. A constituent of the herb, hyperforin, binds to PXR and activates CYP3A4, which initiates drug metabolism in the liver, thereby disarming the contraceptive. Similar interactions between the regulator and otherwise potent AIDS drugs, like Indinavir, and transplant drugs, such as the immunosuppressant cyclosporin, leave them dangerously ineffective. In a similar manner, psolaren from grapefruit juice can inhibit drug metabolism and so interfere with certain medications, such as the antihistamine terfenadine and cyclosporin, leading to dangerously raised plasma levels of these compounds.

The PXR molecule. Click on picture to get 3D interactive view (Chime plugins from MDL is needed).

"Our 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," explains UNC chemist Matthew Redinbo. "This is the first close glimpse into how that is accomplished."

The crystal structure of PXR alone and in combination with the cholesterol-lowering drug SR12813 reveals a large, smooth pocket that can apparently accommodate a wide variety of compounds. Indeed, the SR12813 itself can fit into the PXR pocket in at least three different ways. The team hopes that the revelations seen in the crystal structure of PXR may help them predict and possibly prevent such drug-drug interactions. The team has also discovered that changing just four amino acids in mouse PXR can "humanize" it so that its specificity mimics the natural activity of human PXR. This should help drug-drug interactions be identified using computerized and experimental methods.

Source:
http://www.sciencemag.org/cgi/content/full/292/5525/2329^*

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