Team probes acetaminophen action
by Leigh MacMillan
May 17, 2002
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.
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.
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.”
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
“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.”
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.
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.
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.
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.
colleagues hope their research findings will pave the way toward
a toxicity-free relative of 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.
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.