What the doctor ordered

日期:2017-05-05 04:18:43 作者:农忾怿 阅读:

By Philip Cohen A BIG piece of the puzzle about how the body rids itself of drugs has been discovered by researchers in North Carolina. The study into the workings of a single gene could lead to a laboratory test that predicts how drugs will interact with each other. Some 60 per cent of all medicines are inactivated by a liver enzyme called CYP3A4, and production of this enzyme can be elevated by a surprising variety of medications, including antibiotics, anti-inflammatory steroids and cholesterol-lowering drugs. If a patient onone drug starts to take another that affects this enzyme, doctors may have to increase their dosage of the original drug for it to remain effective. Nearly everyone assumed that the gene for CYP3A4 must have many activating factors, each responding to a different class of drug. But the answer may be far simpler than that, say Steven Kliewer and Jürgen Lehmann at Glaxo Wellcome in Research Triangle Park, North Carolina. They report in this month’s issue of The Journal of Clinical Investigation (vol 102, p 1016) that the different drugs don’t boost the enzyme directly, but instead act on a protein called PXR that acts as a master switch to turn up enzyme production. The researchers already knew that PXR binds to specific genetic sequences that activate the CYP3A4 enzyme’s gene. So they linked these sequences to a “reporter” gene, and then treated cells containing the reporter gene and PXR with a wide variety of chemicals known to amplify CYP3A4 production. To their surprise, every chemical the researchers added boosted the activity of the reporter gene. “That got me really excited,” says Kliewer. “That PXR responds to all these different compounds suggests it really serves as the master switch regulating CYP3A4.” The researchers also found that if PXR wasn’t in the cells, expression of CYP3A4 plummeted. Kliewer says that his team’s simple test-tube assay could be used to predict which new drugs might trigger a surge in enzyme levels. When the interaction between drugs and PXR is better understood, he says, it may also be possible to design drugs that steer clear of PXR and so avoid the problem of activating the gene for CYP3A4 entirely. “This could be tremendously important,” says Fred Guengerich, a biochemist at Vanderbilt University in Nashville,