Acetaminophen / COX-3
Mon Sep 16 NEW YORK (Reuters Health) - Acetaminophen, better known as the active ingredient in Tylenol and certain cold remedies, has been used for more than a century to relieve pain and fever, but exactly how the drug worked was a bit of a mystery. Now, Utah researchers have found that the drug seems to target a variant form of an inflammation-related enzyme.
Ibuprofen, aspirin and other so-called nonsteroidal anti-inflammatory drugs, or NSAIDs, work in part by targeting a pair of enzymes called COX-1 and COX-2. Although acetaminophen relieves pain and fever, unlike NSAIDs it does not have a strong anti-inflammatory effect nor does it target COX-1 and COX-2.
Acetaminophen has "never had a clearly defined mechanism of action," Dr. Daniel L. Simmons, of Brigham Young University in Provo, who led the new research, told Reuters Health in an interview.
But according to Simmons, scientists have suspected that there might be a type of COX enzyme in the brain that is more sensitive to acetaminophen. In experiments in dogs, Simmons and his colleagues seemed to detect two different types of COX-1. This variation of COX-1, which the researchers dubbed COX-3, was most abundant in the brains of the dogs.
Unlike COX-1 and COX-2, this newly discovered enzyme, COX-3, was strongly inhibited by acetaminophen.
"Thus, inhibition of COX-3 in the brain and the spinal cord may be the long sought-after mechanism of action of acetaminophen," Simmons and his colleagues state in a report that is published in the advance online edition of the journal Proceedings of the National Academy of Sciences ( news - web sites).
What's more, Simmons said in the interview, "not only was it sensitive to acetaminophen, it was sensitive to other drugs that have a similar sort of action."
Besides shedding light on the workings of a drug that is a staple of the modern medicine cabinet, the discovery of COX-3 could advance research on pain in general, according to the report. Since the newly identified enzyme is a variant form of COX-1, the fact that COX-3 is blocked by acetaminophen, a pain and fever reliever, suggests that the gene for COX-1 may play an important role in pain and fever.
Simmons and his colleagues also found that besides acetaminophen, several types of NSAIDs inhibited COX-3. This raises the possibility, according to the report, that some of the pain-relieving effects of these drugs might stem from their effect on the newly identified enzyme.
The findings represent a "very interesting and exciting start," according to Simmons, but much more research needs to be done. One of the next steps, he said, is to identify COX-3 in humans and prove that acetaminophen blocks it.
SOURCE: Proceedings of the National Academy of Sciences 2002;10.1073/pnas.162468699. |
