1. Story map

2. Quacky cough medicine?

3. Place for placebo effect?

4. Hip, hyp, hypnotize

5. Worried about St. John's wort

Chinese St. John's Wort. Images: National Agricultural Library

Hypericum perforatum is the most common of the plants commonly called St. John's wort. California Department of Food and Agriculture Botany Lab

St. John's wort was also used to detoxify the liver, which should make sense if you keep reading.

More recently, wort earned a place in the medicine cabinet as a treatment for depression. It's particularly valued in Germany, where folks spend four times as much on it as on the anti-depressant Prozac.

Although a large German analysis published by Linde in 1996 (see "St John's Wort for Depression" in the bibliography) found St. John's wort highly effective in treating depression, recent studies have found it less effective -- but hardly feckless.

Like Germans, Americans have responded to the good news. Jonathan Davidson of Duke University Medical Center says 3.7 percent of depressed Americans have taken wort for at least a month. Davidson has submitted results of a large depression trial of St. John's wort to a journal, but is mum on the results.

Darn. Would be nice to know if the stuff works, especially since, as Davidson points out, this serious mental illness affects between 17 percent and 20 percent of the U.S. population, and is a common cause of suicide.

But many people don't get too lathered up about the subject of wort's real effectiveness. The weed is natural, after all, and natural means safe.

You buy that? You buy wort? Then keep reading.

Is wort wicked?
Lately we've heard some bad news about St. John's wort. Specifically, it may interfere with lifesaving medicines like cyclosporine, used to prevent organ rejection after transplants. Typical doses of St. John's wort also slash blood concentrations of Indinavir, an AIDS drug, by 90 percent.

Wort may be natural, but then so is curare, the secret ingredient in poison arrows.

Natural Safe.
Now we hear from Steven Kliewer, a researcher with the pharmaceutical giant SmithKlineGlaxo, that compounds in wort bind to and activate a receptor called PXR. Kliewer, who is checking out the biochemistry of wort, spoke to the American Association for the Advancement of Science in Boston this February.

The name PXR may be pure poetry, but the fact that this receptor appears in the intestine and liver is one indication that it may help detoxify harmful molecules.

The research was part of a Glaxo search for drugs that interact with nuclear receptors -- proteins in the cell's nucleus that respond to chemical signals by directing DNA to do something -- to make a protein.

Some reception!
Like other biological receptors that have come to light in the past couple of decades, nuclear receptors recognize only specific molecules. Receptors and the molecules that activate them make up a sophisticated chemical signaling system that can reach virtually every cell in the body.

But nuclear receptors are especially prized by drug companies since they are close to the action -- the point where genes make proteins.

Once triggered by a signaling molecule, PXR activates the CYP3A (more bio-poetry!) gene, which makes a protein used by the body's detoxification system. Although the fact that you have an on-board detox system may be news to you, it should be good news.

The detox system uses several types of proteins to rid the body of unwanted molecules:

Oxygenating enzymes start chemical changes that make molecules easier to excrete (generally by making them more water-soluble)

Conjugating agents hook onto the unwanted molecules, changing their chemical properties

Transporters act like tiny freight trains, moving chemicals to the bloodstream or bile

The ultimate goal of these systems is to get the nasties to the kidneys or small intestine, where they can be excreted. Detox systems may attack chemicals formed naturally by the body, or unwanted chemicals we've eaten, inhaled or absorbed.

Detox mechanisms are unquestionably good friends. But what happens if the target molecule is a drug we need to stay alive? Most medicines must, after all, must hang around in the body to be helpful...

Trigger mechanism

Microscopic view of a hypericin-containing gland of St. John's-wort, Hypericum punctatum. Hypericin contains wort's medicinal chemicals. Mary Duke, USDA.

Now we return to St. John's wort. Kliewer has found that one component of wort triggers the PXR receptor, and then the CYP3A gene. When Kliewer began his research, PXR was considered an "orphan receptor," since nobody knew what activated it.

(Down at the Files, we know PXR was an orphan. Would any parent name a kid "PXR"?)

Getting back to our story, a search for molecules that would trigger the CYP3A detoxification mechanism lead Kliewer to St. John's wort, which indeed triggered CYP3A.

Depressed? Confused?
These data don't explain why St. John's wort helps combat depression, which is the major reason people take the wort. So does CYP3A matter?

It would seem that it does. People who are taking lifesaving drugs like Indinavir may be deluded into thinking that because wort is natural, it must be harmless.

Apparently not.

Cornell University graduate student Taran Sirvent prepares dried Hypericum perforatum for extraction and analysis. Photo by Peggy Greb, USDA.

Like synthetic drugs, natural medicines like St. John's wort are treasured precisely because they affect the body. And while the ability to help the body detoxify chemicals is obviously helpful in its place, it could be deadly to those who rely on those chemicals to, say, protect a transplanted heart from immune rejection.

In fact, Kliewer says wort hastens the metabolism (destruction) of a wide variety of medicines. "St. John's wort regulates a whole program of genes involved in solubilization and excretion of chemicals from the body. It's likely to interfere with a wide variety of drugs"-- about half of all prescription drugs!

The story gets even more interesting. The CYP3A-PXR mechanism is also triggered by drugs used to treat epilepsy, diabetes, cancer and inflammation. "You have a situation where a drug can amplify expression of CYP3A, and accelerate the metabolism of other drugs," says Kliewer. It doesn't take a Ph.D. to recognize that this is a recipe for a raft of drug interactions.

Slurp, slurp.
CYP3A is one of the cytochrome P450 proteins, which, like a diligent crew of cleaners and scrubbers, specialize in ridding the body of fat-associated (lipophilic) chemicals. Interestingly, Jacqueline Sinclair, a biochemistry researcher at Dartmouth College, has found that ethanol -- drinking alcohol -- also triggers CYP3A -- increasing the metabolism of drugs.

That, she writes, could explain why heavy drinking clears out medicines from the body. Since the list of meds includes the painkiller acetaminophen, alcohol could explain the liver toxicity associated with that drug.

Our bibliography is certified non-toxic!

©2002, University of Wisconsin, Board of Regents.