May 17, 2002

Team probes acetaminophen action

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Olivier Boutaud, Ph.D., displays a model of acetaminophen. (photo by Dana Johnson)

Team probes acetaminophen action

It douses fever. It blunts pain. But it is powerless against inflammation and clotting. Scientists have long wondered why acetaminophen — the active ingredient in Tylenol — can perform some, but not all, of the functions of aspirin and other similar drugs.

Now, Vanderbilt University Medical Center investigators have an answer. They report in the May 14 issue of the Proceedings of the National Academy of Sciences that acetaminophen works on the same target molecule as aspirin, but that its effectiveness depends on the cell type. In nerve cells, acetaminophen works well; in inflammatory cells and platelets, it is much less potent.

The findings could contribute to the design of better anti-inflammatory drugs, said the study’s lead author, Olivier Boutaud, Ph.D., research assistant professor of Pharmacology.

“We are always looking for the perfect drug — one that is doing what we want and that has no side effects,” Boutaud said. “We are far from that drug.”

While acetaminophen is a successful and widely used drug, it does have undesirable side effects. A single high dose of acetaminophen can be fatal. And chronic use of the drug in some patients can result in liver and kidney damage.

“It’s not a safe drug, and we didn’t know how it works,” Boutaud said. “We thought maybe if we know how it works, we can understand why it’s unsafe, and we can design a safer drug.”

Boutaud and colleagues Dr. David M. Aronoff, instructor in Medicine, and Dr. John A. Oates, Thomas F. Frist Professor of Medicine, set out to determine how acetaminophen works. They confirmed what the scientific community assumed was true — acetaminophen works, like aspirin and other non-steroidal anti-inflammatory drugs, by blocking the activity of the cyclooxygenase (COX) enzyme.

But acetaminophen works a little differently to block COX activity. Aspirin, ibuprofen, indomethacin, and other NSAIDs insert into the COX active site — like the wrong key being stuck into a lock. Because they are in the way, the COX enzyme cannot do its normal job of producing prostaglandins.

Acetaminophen doesn’t fit into the lock. Instead, it disrupts the activation of COX by another enzyme activity, a peroxidase, within the same protein. Because this activation is necessary for COX activity, the end effect of acetaminophen and other NSAIDs is the same.

Chemicals called peroxides, though, drive the activation of COX and can overcome the effect of acetaminophen. Because platelets and immune cells generate high levels of peroxides, Boutaud said, acetaminophen doesn’t work well in these cell types. Brain and endothelial cells that participate in fever and pain do not have high levels of peroxides, and acetaminophen is effective in these cells.

Boutaud and colleagues hope their research findings will pave the way toward a toxicity-free relative of acetaminophen.

“Acetaminophen is a very good drug for fever and pain — we aren’t necessarily trying to design a drug that works better than it does, but one that is free of the toxic side effects,” Boutaud said.

Other collaborators on the PNAS paper include Jacob H. Richardson and Lawrence J. Marnett, Ph.D. The research was supported by grants from the National Institutes of Health and Merck-Frosst Canada and Company.