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How the Body’s ‘Garbage’ Disposal May Inactivate Drugs: A protein sentry that

triggers the liver’s defense against chemical toxins can explain drug

interactions – and an old legend.

 

Some 2000 years ago, King Mithridates of Pontus, a region on the Black Sea that

is now part of Turkey, performed an astonishing trick. According to a legend

immortalized in an A.E. Housman poem, the ambitious and warring monarch feared

his enemies would poison him. To guard

against this, he dosed himself with small amounts of poisons to build up his

immunity. The technique worked: Mithridates survived and his name came to mean

an antidote for poison.

Molecular endocrinologists now think that they have a molecular explanation for

Mithridate’s invulnerability. Recent work at the Salk Institute for Biological

Sudies in La Jolla, and by other teams around the world is revealing the

machinery of the body’s defense against poisons

and other foreign chemicals. The work, reported over the year, helps explain not

only an ancient riddle but also why taking certain drugs or herbs, like the

popular St. John’s Wort, can render others ineffective.

Scientists have known for years that the body has a chemical surveillance system

in the liver. Sensing the presence of potentially dangerous chemicals, the liver

cells crank up the production of an enzyme called CYP3A, which breaks down a

host of compounds, including many toxins.

Essentially, CYP3A is the liver’s garbage disposal.

Many scientists suspect that this ‘garbage disposal’ evolved to fend off the

countless toxins to which animals are exposed in the environment, including the

poisons plants produce to avoid being eaten. But exactly how it works has loon

been a mystery. A key question is what

receptors in the liver cell initially sense the toxin and alert the chemical

police to seek and destroy it. Most scientists expected to find a suite of

receptors, all tailored to recognize specific threats. But over the past few

months, converging research by several teams

suggests that just one protein – perhaps aided by a handful of assistants – can

recognize the thousands or even tens of thousands of potentially harmful

compounds present in the environment and prompt the liver to mount an all-out

attack on them.

One set of clues came from an unexpected line of research: Patients taking St.

John’s Wort, a popular herbal remedy for depression. In late 1999 and early

2000, several papers reported that in some half-dozen patients taking this herb,

the blood concentrations of other drugs they

were taking – including the asthma drug theophylline and the anti-clotting drug

warfarin – were dramatically reduced. Several women taking birth control pills

reported breakthrough bleeding, suggesting that the pill’s hormone levels had

dropped. In another well-publicized example,

two heart transplant recipients in Germany experienced life-threatening

transplant rejections of a few weeks after starting to take St. John’s Wort.

Their physicians found that levels of the immunosuppressant cyclosporin had

plummeted to half the normal dose. (see attached

sidebar, below)

Many scientists suspected that the herb was activating the CYP3A pathway, which

would accelerate the breakdown of the other drugs. Intrigued, several

researchers decided to test whether the herb was working through the PXR

receptor, a protein they had discovered in mice several

year earlier and had been intensely studying ever since. They knew that PXT,

which has a human counterpart known as SXR, triggered production of CYP3A. But

they did not know what activated PXR in the first place. A GlaxoSmithKline

headed off to the local pharmacy and bought three

preparations of the herb. When their effect was tested on the PXR, they hit

paydirt. They found that it was extremely efficient at activating PXR. The team

tested several active components of the herb and found that almost all the PxR

activity was caused by a molecule called

hyperforin – the same compound that many scientists think bestows the herbs

antidepressant activity. St. John’s Wort, it seems, triggers PXR, which cranks

up production of the CYP3A enzyme, which in turn breaks down cyclosporin,

idinavir, and a host of other drugs.

What’s more, PXR seems to be almost solely responsible for activating the

chemical police system. The evidence come from experiments with knockout mice

done to further characterize PXR. In July, 2000, one group reported that mice

lacking the PXR gene did not respond to compounds

that typically kick off the CYP3A system in mice. But when the researchers

knocked out PXR and inserted SXR, the animals had a ‘humanized’ CYP3A response:

They still failed to respond to classic triggers of the mouse CYP3A system, but

they reacted strongly to at least a dozen

compounds that activate the human system, including the antibiotic rifampicin –

notorious for triggering drug interactions. Because switching a single gene

caused such a dramatic change, it argues that PXR and SXR are the primary

sentries for the CYP3A system. The overall system

may be a lot simpler than researchers first thought.

There is evidence that SXR does not work entirely alone, however. In October, a

team at Baylor College of Medicine in Houston, reported that another gene called

CAR seems to play a similar role, activating an enzyme called cYP2B in response

to Phenobarbital. CYP2B, in turn, breaks

down a number of compounds, including cocaine. But research suggests that it

seems to have a narrower scope that SXR.

No one yet understands how SXR and PXR can respond to so many different

chemicals. Some suspect that the receptor may have an especially large binding

site, which can accommodate a variety of molecules. To test that theory,

scientists must obtain the crystal structures of the

receptor with many different ligands – a daunting project that several teams are

working on.

No matter how the receptor works, some scientists predict that the humanized

mouse model will be a boon to pharmaceutical companies. By testing compounds in

these knockout mice, companies can determine which ones activate the CYP3A

system and thus potentially interfere with other

medications. Companies today use cultured human cells to test for a range of CYP

gene activation, but such tests may be more variable than a humanized mouse

might be. Others are not convinced, however. Some suspect that research will

uncover additional receptors, such as the CAR

gene, that play an important role in drug interaction.

 

However many receptors are involved, the defense system worked for Mithridates –

if the legend can be believed. Investigators theorize that the small does of

poison Mithridates ingested primed his SXR receptor. With the CYP3A system on

high alert, otherwise deadly doses were

easily neutralized. As A.E. Houseman described it:

 

The put arsenic in his meat

And stared aghast to watch him eat;

They poured strychnine in his cup

And shook to see him drink it up;

They shook, they stared as white’s their shirt:

Them it was their poison hurt.

- I tell the tale that I heard told.

Mithridates, he died old.

 

 

A Worrisome Side Effect of an Antianxiety Remedy: As reports came in on drug

interactions with St.John’s Wort, the NIH and the FDA went on alert. In February

2000, NIH scientists reported in The Lancet tat, in healthy volunteers, St.

John’s Wort cut in half the blood levels of the

antiretroviral drug idinavir commonly used to treat HIV infections. In the same

issue, German doctors reported that the herb had caused levels of an

immunosuppressant drug to plummet in two heart transplant recipients. That week,

the FDA issued an official warning to doctors and

pharmacists noting that the herb could interfere with dozens of drugs, including

the antiseizure medication Phenobarbital, the breast cancer drug tamoxifen, and

oral contraceptive ethinyl estradiol, and antiretrovirals used to treat AIDS.

As scientist discovered a few months later, the herb triggers production of an

enzyme called CYP3A, which breaks down potential toxins in the liver. In

addition to warding off poisons, the CYP3A system also helps to metabolize

hormones such as estrogen, testosterone, and their

precursors. For that reason, the FDA now warns that women taking birth control

pills should not take St. John’s Wort, because CYP3A breaks down the synthetic

hormone designed to prevent pregnancy. No one, however, has done a systematic

study of the pill’s failure rate in women

taking the herb.

The work has uncovered an unexpected potential benefit as well. The latest work

by team at GlaxoSmithKline and the Salk Institute, shows that the CYP3A system

also helps break down bile acids. Researchers believe that the herb might be

useful in alleviating an especially

difficult-to-treat condition called cholestasis. This condition occurs when

people can’t break down bile acids properly and toxic byproducts build up in the

liver.

 

(Adapted from: Science, Vol 291, 5 January 2001. pp. 35-37.)

 

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