A Traditional Remedy That Disables a Drug-Clearing Enzyme

Roughly half of all prescription drugs are broken down in the body by a single liver enzyme, cytochrome P450 3A4, usually abbreviated CYP3A4. Most substances that interfere with this enzyme do so reversibly: they temporarily occupy the site where the enzyme works and release it once the substance clears the body. A smaller, more consequential category, known as mechanism-based inactivators, works differently. Here, the enzyme itself converts the substance into a reactive form that binds permanently to CYP3A4, destroying it outright. Because the body can only restore enzyme activity by synthesizing new CYP3A4 from scratch, recovery from this kind of inactivation can take several days, far longer than recovery from an ordinary reversible interaction. Grapefruit juice is the most widely known example, but a 2011 study testing seventeen plants used in traditional Cree medicine to manage type 2 diabetes found that several, including the clubmoss Lycopodium clavatum, act as potent mechanism-based inactivators of CYP3A4 as well. This matters beyond the laboratory: many of the same patients who use these plants alongside prescription diabetes medication are relying on drugs, including certain oral diabetes treatments and blood pressure medications, that CYP3A4 is largely responsible for clearing from the body. A plant that quietly disables the enzyme can leave a prescription drug circulating at unpredictable, potentially unsafe levels.