15.4: No Pain, Your Gain

Like curare's effects on acetylcholine, the interactions between another drug—aspirin—and metabolism shed light on how the body works. This little white pill has been one of the most widely used drugs in history, and many say that it launched the entire pharmaceutical industry.

As a prescribed drug, aspirin is 100 years old. However, in its most primitive form, aspirin is much older. The bark of the willow tree contains a substance called salicin, a known antidote to headache and fever since the time of the Greek physician Hippocrates, around 400 B.C. The body convents salicin to an acidic substance called salicylate. Despite its usefulness dating back to ancient times, early records indicate that salicylate wreaked havoc on the stomachs of people who ingested this natural chemical. In the late 1800s, a scientific breakthrough turned willow-derived salicylate into a medicine friendlier to the body. Bayer® scientist Felix Hoffman discovered that adding a chemical tag called an acetyl group (see figure, page 20) to salicylate made the molecule less acidic and a little gentler on the stomach, but the chemical change did not seem to lessen the drug's ability to relieve his father's rheumatism. This molecule, acetylsalicylate, is the aspirin of today.

Aspirin works by blocking the production of messenger molecules called prostaglandins. Because of the many important roles they play in metabolism, prostaglandins are important targets for drugs and are very interesting to pharmacologists. Prostaglandins can help muscles relax and open up blood vessels, they give you a fever when you're infected with bacteria, and they also marshal the immune system by stimulating the process called inflammation. Sunburn, bee stings, tendonitis, and arthritis are just a few examples of painful inflammation caused by the body's release of certain types of prostaglandins in response to an injury.

Inflammation leads to pain in arthritis.

Aspirin belongs to a diverse group of medicines called NSAIDs, a nickname for the tongue-twisting title nonsteroidal antiinflammatory drugs. Other drugs that belong to this large class of medicines include Advil®, Aleve®, and many other popular pain relievers available without doctor's prescription. All these drugs share aspirin's ability to knock back the production of prostaglandins by blocking an enzyme called cyclooxygenase. Known as COX, this enzyme is a critical driver of the body's metabolism and immune function.

COX makes prostaglandins and other similar molecules collectively known as eicosanoids from a molecule called arachidonic acid. Named for the Greek word eikos, meaning "twenty," each eicosanoid contains 20 atoms of carbon.

You've also heard of the popular pain reliever acetaminophen (Tylenol®), which is famous for reducing fever and relieving headaches. However, scientists do not consider Tylenol an NSAID, because it does little to halt inflammation (remember that part of NSAID stands for "anti-inflammatory"). If your joints are aching from a long hike you weren't exactly in shape for, aspirin or Aleve may be better than Tylenol because inflammation is the thing making your joints hurt.

To understand how enzymes like COX work, some pharmacologists use special biophysical techniques and X rays to determine the three-dimensional shapes of the enzymes. These kinds of experiments teach scientists about molecular function by providing clear pictures of how all the folds and bends of an enzyme—usually a protein or group of interacting proteins—help it do its job. In drug development, one successful approach has been to use this information to design decoys to jam up the working parts of enzymes like COX. Structural studies unveiling the shapes of COX enzymes led to a new class of drugs used to treat arthritis. Researchers designed these drugs to selectively home in on one particular type of COX enzyme called COX-2.

By designing drugs that target only one form of an enzyme like COX, pharmacologists may be able to create medicines that are great at stopping inflammation but have fewer side effects. For example, stomach upset is a common side effect caused by NSAIDs that block COX enzymes. This side effect results from the fact that NSAIDs bind to different types of COX enzymes—each of which has a slightly different shape. One of these enzymes is called COX-1. While both COX-1 and COX-2 enzymes make prostaglandins, COX-2 beefs up the production of prostaglandins in sore, inflamed tissue, such as arthritic joints. In contrast, COX-1 makes prostaglandins that protect the digestive tract, and blocking the production of these protective prostaglandins can lead to stomach upset, and even bleeding and ulcers.

Very recently, scientists have added a new chapter to the COX story by identifying COX-3, which may be Tylenol's long-sought molecular target. Further research will help pharmacologists understand more precisely how Tylenol and NSAIDs act in the body.