Acetaminophen, the active ingredient in Tylenol, is among the world's most popular pain medicines, but, agonizingly enough for researchers, how it works has been largely a mystery. Now a group has discovered an enzyme that fits the profile of the long-sought site of action for the drug: a new variant of the well-studied cyclooxygenase (COX) enzymes.
For decades, scientists thought that only one form of COX existed. But in 1991, three independent research teams unveiled a second form, COX-2, and showed that it is the enzyme primarily responsible for inflammation. The first form, COX-1, safeguards the stomach lining, among other housekeeping jobs. Aspirin, ibuprofen, and other nonsteroidal anti-inflammatory drugs inhibit both COX-1 and COX-2. But neither enzyme could explain the action of acetaminophen, which inhibits both molecules only very weakly.
Biochemist Daniel Simmons of Brigham Young University in Provo, Utah, happened upon COX-3 serendipitously while trying to develop a better painkiller for dogs. He and his team were startled to find two genetic footprints, in the form of messenger RNAs (mRNAs), for COX-1 in dog brain. As the researchers report online 16 September in the Proceedings of the National Academy of Sciences, one of the mRNAs contained an additional short section of genetic code that is clipped out of COX-1.
When Simmons and colleagues inserted the genetic code into insect cells, the cells produced novel enzymes that, like known forms of COX, churned out inflammatory molecules. The researchers exposed the COX-3-bearing insect cells to various painkillers and to their astonishment found that acetaminophen almost completely inhibited the new enzyme. Simmons's team also found preliminary evidence that COX-3 exists in humans and is particularly plentiful in brain tissue.
The find "could explain the effects of acetaminophen, which we've never understood," says Timothy Warner, a pharmacologist at Barts and The London School of Medicine and Dentistry in the United Kingdom. He cautions that much more work needs to be done to determine COX-3's role in the human brain, if any. But if the finding holds up in humans, it might portend the presence of other COX variants and lead to pain and fever relievers that are better tailored to individual patients or ailments.