Delicious Grapefruit Juice Causes Your Liver to 'Commit Suicide' - A Biochemical Allegory

Is there anything more delicious than a cold glass of fresh grapefruit juice on a warm summer day? Unfortunately, many of you cannot partake in such a tempting treat because you're taking one of roughly 100 different medications. Here's why.

Grapefruits evolved a defense mechanism against insects, microbes, and UV radiation. They achieve this by biosynthesizing a group of chemicals called furocoumarins, the most significant of which is bergamottin. That's great for the plant but not so much for people who are taking the meds and crave the juice.

And it just so happens that the mechanism—the inhibition of key liver enzymes—that helps the plant protect itself is also responsible for drug-drug interactions in humans (1), but in an even more extreme way. Bergamottin doesn’t just inhibit oxidative liver enzymes (CYPs); it actually tricks them into destroying themselves. The biochemistry term "suicide enzyme inhibitor" is a fairly accurate portrayal of what's going on.

CYPs are your body's oxidative metabolism workhorses

Here's a brief look at CYPs, starting with the name (in living color).

Cytochrome P450 enzymes (CYPs) are a family of proteins that play the key role in metabolizing drugs, toxins, and endogenous biomolecules. They do so by catalyzing oxidation reactions. This enables the body to chemically modify and eliminate substances—essentially serving as the liver's biochemical cleanup crew. We would be magnificently dead without them. 

Why bergamottin is verboten?

Unfortunately, bergamottin makes grapefruit verboten for people who take certain drugs because it also happens to strongly inhibit CYP3A4, the most important member of the CYP family responsible for metabolizing drugs. (Figure 1)

(Left) A ribbon diagram of a typical CYP enzyme. The green structure in the middle (highlighted by the yellow circle) is where heme resides. Its sole purpose is to hold an iron atom – the key to the whole process – in place, where it can oxidize a substrate. (Right) Inside the yellow circle: Iron bound to heme. Image: Wikipedia.

Plenty of medicines—and even some foods and drinks—cause clinically significant CYP inhibition, but few do it in such a uniquely sinister way.  CYP3A4, perhaps the most important oxidative enzyme in humans, accomplishes a lot, but has neither the self-awareness or ability to dial a suicide hotline when a molecule of bergamottin pays a call. A simple chemical reaction tricks it into self-destruction, leaving you stuck with something putrid—like a Diet Pepsi—instead of the juice.

How does this strange reaction work?

I'm always reluctant to mention the terms "suicide" and "chemistry" in the same article, but there is no getting around it here. This is what happens when CYP3A4 is the unfortunate recipient of its final work assignment. Ever. 

Step 1. The "tastiest" part of bergamottin is the furan ring (the explanation is beyond the scope of this article). CYP3A4 converts the furan double bond into a reactive 3-membered ring called an epoxide; much what you'd expect. Well, maybe not you.

Step 2. Epoxides are potent electrophiles, meaning they crave electron-rich functional (a.k.a. nucleophilic) groups like amines and thiols. All proteins—including CYP3A4—are made up of amino acids, some of which contain these reactive groups. One of CYP3A4’s nucleophilic side chains quickly sniffs out the promiscuous epoxide—sort of like swiping right on Molecular Tinder—and they hook up.

Only, this hookup is anything but a one-night stand. The covalent adduct is stable, meaning Mr. Bachelor 3A4’s single days are officially over. The enzyme is effectively dead, consigned to the detritus of human and molecular waste—much like many macromolecular marriages.

How far you want to stretch the human analogy is up to you. Maybe it's just a quirky way to explain a suicide enzyme inhibitor. Or maybe it’s a dark little fable about loyalty, bad decisions, and the dangers of molecular infidelity. Either way, the next time you reach for grapefruit juice, think twice—it’s both a Greek tragedy and a breakfast beverage.