By David N. Leff

¿St. John¿s wort babies¿ are not wards of some faith-based charity.

Rather, explained structural biologist Matthew Redinbo, at the University of North Carolina, Chapel Hill, ¿If you take the unregulated herbal remedy St. John¿s wort at the same time as an oral contraceptive, there¿s some indication that St. John¿s wort leads to the metabolic breakdown of the Pill. So there¿s a catchphrase in the field that there are these St. John¿s wort babies running around who were conceived unintentionally by these drug-drug interactions.¿

Although unapproved by the FDA, St. John¿s wort (Hypericum perforatum) is widely sold in health food stores and pharmacies as a mild antidepressant, sedative and anxiolytic. One of its constituents, hyperforin, induces the body¿s cytochrome P450 enzyme system, a major pathway for cyclosporin metabolism.

¿Say you¿re taking the immunosuppressant cyclosporin,¿ Redinbo continued, ¿a drug that¿s intended to keep you alive if you happen to be receiving a lung or kidney organ transplant. But if you¿re also taking St. John¿s wort on the side, that herbal remedy can upregulate cytochrome P450 expression and break down cyclosporin ¿ thus threatening your survival.¿

Similarly, St. John¿s wort taken together with the HIV retroviral antiprotease, Crixivan (indinavir), produces drug resistance and treatment failure in patients. But the herbal remedy is not the perpetrator of these dangerous drug interactions. Rather, it¿s one example of the innumerable foreign drugs and toxins ¿ xenobiotics ¿ that cause such foul-ups.

¿A xenobiotic is any compound that is not endogenous to the body,¿ Redinbo said. He is senior author of a paper in the current Science, dated June 15, 2001, titled: ¿The human nuclear xenobiotic receptor PXR: Structural determinants of directed promiscuity.¿ Seven of its nine co-authors are scientists at GlaxoSmithKline nuclear receptor discovery unit in Research Triangle Park, N.C. Among them is molecular endocrinologist Steven Kliewer, who discovered PXR in a mouse three years ago.

PXR, the human nuclear ¿pregnane X receptor,¿ activates cytochrome P450-3A expression in response to a vast variety of xenobiotics. It plays a critical role in mediating harmful drug-drug interactions. Pregnane, Redinbo explained, ¿is a set of biologic precursors that bind to a bunch of xenobiotics ¿ exogenous compounds ¿ even to some endogenous compounds generated within the body.¿

Crystal Structure Solves PXR¿s Promiscuity

PXR¿s job in the mammalian body is to look for potentially harmful drugs and toxins, then activate the enzyme that breaks them down for excretion. ¿PXR is the master regulator of P450-3A,¿ Redinbo pointed out,¿ which breaks the medications down. Like an electric switch, it turns on and off the machinery that metabolizes 60 percent of all drugs used, so it¿s critically important to human health.

¿Unraveling the crystal structure of one of the body¿s most critical drug detectors ¿ the human pregnane X receptor ¿ could improve our ability to predict and avoid those deadly drug-drug interactions. PXR is highly promiscuous,¿ he went on, ¿meaning that it binds to dozens of well-known drugs and toxins, including the antibiotic rifampicin, the anticancer drug taxol and the abortion pill RU-486. These compounds vary in size and shape, but PXR can handle them all.

¿The structural question we were trying to answer in our Science article,¿ he observed, ¿was how does one molecule, one protein, bind to dozens and dozens of different drugs that it would encounter in the body? We determined that PXR has a really big binding cavity in its atomic structure that¿s pretty smooth in shape. But it uses about five different polar amino-acid side chains.

¿There¿s a critical difference between PXR¿s structure in humans and in other mammals,¿ Redinbo pointed out. ¿Humans were evolved with a certain amount of chemical pressure put on them. As we¿ve been living and evolving we¿ve encountered thousands and thousands of xenobiotics that might challenge our survival. Mice and rats, on the other hand, evolved with different xenobiotic pressure. So they¿re down mucking around in the dirt, and experiencing different things.

¿Current practice in avoiding drug-drug interactions,¿ Redinbo allowed, ¿consists of careful monitoring by physicians. There¿s no good rapid way to screen a priori for interactions. To screen in vitro for this type of interaction, Glaxo¿s utilization of our finding is in development right now.

¿The more experienced and knowledgeable your pharmacist and your clinician are, the better. But I think there¿s a lot that the pharmaceutical industry can do to check this thing out ahead of time. In terms of the crystal structure my group reported,¿ Redinbo suggested, ¿I think there¿s a potential for in silico or computer screening of drugs to see whether or not they may activate this PXR receptor. You can combine that with some in vitro stuff other people have developed that may be a powerful combination.

¿The university has filed a provisional patent application, and we are working with Glaxo,¿ Redinbo observed. ¿Obviously, a lot of the questions I¿m addressing are very academic, and obviously Glaxo is addressing some more commercial aspects.¿

How Glaxo Hit On PXR Plus Drug Interaction

¿The group I work in,¿ Glaxo¿s Steven Kliewer told BioWorld Today, ¿studies steroid hormone receptors. Rather than being therapeutically oriented, we research new members of this family, because to date every one of these receptors has important drug discovery implications.

¿We were not specifically trying to understand drug-drug interactions,¿ he pointed out. ¿We came at this through serendipity.

¿What we found was an interesting member of the family from a mouse, and screened it looking for compounds that modulated this receptor. What we found was that many of the compounds that tested positive were known to have drug-drug interactions. That was the aha¿ moment.

¿So then we went back and showed that this receptor could regulate the genes that are known to be involved in interactions ¿ these cytochrome P450s. And that laid the groundwork for the story. We¿re making use of the PXR system in Glaxo¿s own drug discovery program,¿ Kliewer concluded, ¿in order to eliminate compounds that might suffer from this class of drug-drug interaction.¿

¿This work is likely to become important clinically,¿ Redinbo suggested, ¿because drug companies have been clamoring to know how the human body recognizes their drugs and marks them for degradation. Our work,¿ he concluded, ¿provides the first close glimpse into how that is accomplished.¿

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