Drug And Alcohol Metabolism: The Human Cytochrome System

More than two decades ago, a young man came home from a night of hard drinking and took the drug, acetaminophen, for his hangover. The next day, he was in surgery undergoing an emergency liver transplant. He successfully sued the makers of Tylenol for the liver damage he sustained. Sometime later, a man from a northern state retired to Florida. He bought a house with citrus trees in his back yard, one of them a grapefruit tree. Every day, he enjoyed two large glasses of fresh grapefruit juice. He nearly lost his life from a suspected overdose of his blood pressure medication.

One of the human body's most fascinating and miraculous functions is its ability to process and eliminate the biotoxins we regularly ingest. For this purpose, nature has endowed us with a superfamily of highly specialized proteins called P-450 cytochromes. When most of us think of the word, metabolism, we think of the body's process of turning the food we eat into energy. However, getting rid of biotoxins also requires a form of metabolism to render them harmless. This process is known as P-450 metabolism. It is also known as monooxygenase metabolism – not such a scary word once it's broken into parts. Mono means “single.” Oxygen, we all know that one. The suffix, -ase always refers to an enzyme; enzymes are often catalysts, that is, they are triggers that make other things happen. The process of monooxygenase metabolism starts with a molecule of oxygen – O2. Most of the prescription drugs we take are recognized by our bodies as toxins. This is no accident. Many drugs are designed that way so they can be metabolized for use by one or more P-450 enzymes. Were it not for this system, the drug would simply sit in the liver or other organ and accumulate to toxic levels. The P-450 enzyme causes the breakdown of an oxygen molecule. One of the oxygen atoms in O2 attaches itself to the drug. The other O atom joins with two hydrogen atoms to make H2O – water. The drug is then dissolved in the water and carried through the body. So, two single (mono) oxygen atoms undergo transformation by an enzyme: monooxygenase. This is a simplified explanation of P-450 metabolism.

The liver is well-known as a detoxifying organ, but when the liver is damaged, the amount of available P-450 proteins may become fewer, slowing the detoxification process. This is why it's so important for liver patients to keep a current list of medications, both prescribed and over-the-counter, as well as vitamins and supplements – nearly all of these require metabolism in the liver by P-450 cytochromes. When large amounts of liver tissue become unavailable because of fibrosis and cirrhosis, the more easily the liver can become overwhelmed. P-450 enzymes are further classified into a number-letter-number system. Different drugs require different enzymes. Example: the cytochrome responsible for handling alcohol is named 2E1. Now, there is only so much 2E1 to go around. The more damage to the liver, the less it is able to metabolize alcohol. Without metabolism, alcohol accumulates in the liver. The man who required the emergency liver transplant had ingested not only alcohol, but also acetaminophen. Both require 2E1 to metabolize. In his case, a lack of sufficient amounts of 2E1 caused the acetaminophen to accumulate in his liver – it nearly killed him. That's because 2E1 seems to have an affinity for solvents – in this case, benzene. Acetaminophen is structured around a molecular ring of benzene.

Perhaps the most important P-450 cytochrome is known as 3A4. It is the most easily induced, and most abundant of all. For this reason, huge numbers of drugs rely on this cytochrome for safe metabolism. So mythical and magical is 3A4 (our bodies seem capable of inducing endless amounts of the enzyme) that many pharmaceuticals are, from their inception, designed to target 3A4. Reliance on this enzyme has become so universal, the FDA has all but outlawed any new drug that inhibits 3A4. In fact, most of the protease inhibitors that destroy the hepatitis C virus rely on 3A4. The most notorious inhibitor of 3A4: grapefruit juice – this explains the near-death experience of the patient mixing grapefruit and his blood pressure medication. When a prescription bottle is labeled with a warning against drinking grapefruit juice with that particular drug, it means that grapefruit will inhibit metabolism, making the drug either ineffective, or poisonous. It's a warning that should be taken seriously. Another well-known inhibitor of 3A4: St. John's wort. Harvoni carries a warning against taking this herbal supplement with Gilead's drug (there are plenty of anti-depressants that do not inhibit 3A4).

The purpose of this article is to introduce hep C patients to the basic science of drug and alcohol metabolism, and drug interaction. For a better understanding of pharmaceutical metabolism and their required cytochromes, an exhaustive P-450 chart from Indiana University is available here.