Putting the squeeze on grapefruit juice.

Quaffing a glass of grapefruit juice boosts the potency of a wide variety of drugs, as many studies have shown. Scientists think that one or more compounds in the juice incapacitate an enzyme that breaks down drugs, effectively increasing the amount of medicine available to the body--sometimes with dangerous consequences.

Now, researchers at the University of Michigan and Parke-Davis Pharmaceutical Research, both in Ann Arbor, have identified a compound in grapefruit juice called bergamottin that could be responsible for the effect. In the test tube, bergamottin inactivates cytochrome P450 3A4, a digestive enzyme that metabolizes many drugs, ranging from antihistamines to medications for high blood pressure (SN: 5/24/97, p. 327).

The finding builds on previous research, done in collaboration with scientists at Wayne State University in Detroit, that isolated a derivative of bergamottin and found that it inactivates the enzyme. Using improved separation techniques, the Michigan team discovered that bergamottin was not only more abundant than its derivative but more effective at shutting down the enzyme.

The researchers report their findings in the April Chemical Research in Toxicology.

Many drugs are metabolized in the intestines before they can enter the blood. Therefore, the compounds responsible for the action of grapefruit juice might be harnessed to reduce the effective dosage, says study coauthor Paul F. Hollenberg of Michigan. Moreover, individuals absorb drugs with varying efficiency, depending on the amount of cytochrome P450 3A4 they have. Knocking out the enzyme could make actual dosages more uniform, he suggests.

Bergamottin is "an important lead, but the jury is still out" on whether it causes the grapefruit juice effect, says David G. Bailey of the University of Western Ontario in London. Other compounds that inhibit the enzyme in the laboratory don't reproduce the juice's effect on drugs taken by people.

Bailey and his colleagues first stumbled across the grapefruit juice effect in 1989, while studying how alcohol interacts with a drug called felodipine, used to treat high blood pressure. When they gave grapefruit juice to their volunteers to mask the taste of the alcohol, the researchers found four times the expected amount of felodipine in their blood (SN: 2/9/91, p. 85).

Bailey conducted a pilot study on himself, taking the drug with either grapefruit juice or water and then measuring concentrations of the drug in his blood. "Lo and behold, my levels were five times higher with grapefruit juice," he says. Further studies confirmed his hypothesis. "When we first reported it, no one believed us. It's so off-the-wall."

Knowing the pharmacology of felodipine, Bailey reasoned that cytochrome P450 3A4 was involved. The enzyme metabolizes about 60 percent of all drugs, making them more easily soluble in water so they can be flushed out of the body.

In the new study, the Michigan researchers used ethyl acetate, an organic solvent, to extract some of the chemicals in freshly squeezed grapefruit juice. They found a high concentration of bergamottin in the mix.

In contrast, orange juice extracts didn't contain bergamottin at all--in accordance with the observation that orange juice doesn't cause the same drug effects.

Bergamottin appears to cause irreversible changes in cytochrome P450 3A4 in the region where it binds drugs, says study coauthor Kan He of Michigan. Additional experiments should reveal more details of that inactivation.

The ultimate proof will come from human tests of bergamottin to see if it can reproduce the grapefruit juice effect, says Bailey.