How does St. John’s Wort Interact with Drugs? Q and A with Dr. Gurley

Hello. My name is Dr. Bill Gurley. I’m a
professor of pharmaceutical sciences in the College of Pharmacy at the University of Arkansas
for Medical Sciences in Little Rock, Arkansas. Clearly, one of the most problematic is St.
John’s wort, and the reason for that is that there’s a unique compound in St. John’s
wort called hyperforin, and what hyperforin does is that it acts with a particular protein
in the cell that, when they come together, this protein is called an orphan nuclear receptor,
specifically one called steroid xenobiotic receptor. And when hyperforin binds to the
steroid xenobiotic receptor in humans, then it goes to—that combination goes to the
nucleus and literally acts as a transcription factor and turns on the genes for many of
the very important human drug metabolizing enzymes.
By doing such, then other drugs that may be taken in conjunction with St. John’s wort
are metabolized more readily, more extensively. And so a lot of this induction of these enzymes—and
transporters, in some instances—by St. John’s wort occurs both in the intestine and in the
liver. And by doing so, if you’ve taken St. John’s wort and you’ve got these enzymes
and transporters induced in the intestine and in the liver, and if you take a drug concomitantly
that’s also a substrate for those enzymes and transporters, then more of that—there’s
more enzyme there to metabolize the drug, and so less drug gets absorbed or less drug
gets past the GI tract or gets past the liver to the systemic circulation. And so what St.
John’s wort does is it renders most medications less effective, sometimes completely ineffective.
So that’s probably the most important one to know in terms of reducing the effectiveness
of medications. And it’s been known for a while, but it never surprises me as that
the news hasn’t gotten out. St. John’s wort affects roughly half of
all conventional medications. And the reason I say that is because the enzymes and transporters
that it boosts the activity of or that it increases the expression of—about half of
all conventional medications are substrates for those. One of the most important enzymes
that it affects is one called cytochrome P450 3A4. And 3A4 is responsible for the metabolism
of roughly half of all conventional medications to some extent. So by inducing the activity
of 3A4, you certainly affect a large number of medications, many of which have what we
call narrow therapeutic indices, which means that the difference between a safe dose and
a toxic dose is pretty small. And so some classic examples that St. John’s wort affects,
and some of the ones that were—that first brought it to the forefront―are the immunosuppressive
drugs for solid organ transplantation, like cyclosporine or tacrolimus. And so what St.
John’s wort does is it renders those very important immunosuppressive agents that allow
transplant organs to keep their transplanted organ from being rejected—it makes them
more susceptible to being rejected because the concentrations of those immunosuppressants
are now well below what’s necessary to make sure that they don’t reject.
A wide variety of other medications, a lot of cardiovascular medications are adversely
affected, a lot of the antihypertensive medications are adversely affected. When I say adversely
affected, I mean rendered less effective. Birth control pills. Certainly the ramifications
of that can certainly be understood. And then a lot of cancer chemotherapeutic agents that
are substrates for these enzymes and transporters can be rendered less effective.
So it—the spectrum of drugs affected by St. John’s wort is fairly broad and the
reason for that is because that orphan nuclear receptor, SXR, or steroid xenobiotic receptor,
whatever you want to call it, is very promiscuous, which means that a lot of drugs—or it can
turn on, it can turn on a lot of enzymes responsible for metabolism of a wide variety of medications.
That’s just a partial list, but it’s a very, very long list of medications that are
affected by St. John’s wort. It’s probably the—it probably affects more drugs from
an herb-drug interaction perspective than any other botanical that we know of so far.

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