Canine brains express new COX enzyme

Provo, Utah-On a mission to probe dogs' brains for clues on how to enhance nonsteroidal anti-inflammatory drugs, Dr. Daniel Simmons and team may have accidentally unlocked the magic of acetaminophen.

Until now, acetaminophen, a drug popularly prescribed for human use,has been little understood by the physicians who recommend it. Via new research,Simmons, a biochemistry professor, and his team from Brigham Young University,suggest the functions of acetaminophen may be capsulized in a variationof an enzyme not seen before.

The new cyclooxygenase variant enzyme, is called COX-3, third in a lineof succession of enzymes that play key roles in the mechanics of variouscommonly-used drugs, says Simmons who collaborated with colleagues on thediscovery.

"We have found a previously unidentified enzyme that is inhibitedby acetaminophen," says Simmons, whose study is reported in the journalProceedings of the National Academy of Sciences.

The researchers tested the new enzyme against pain-relieving drugs andnoticed that it was sensitive to acetaminophen and other similar drugs.Simmons then looked for the new enzyme, COX-3, in human tissue and foundit expressed at the highest levels in the heart and brain.

Building on discovery

Simmons is senior author of a study that sheds welcomed light on howacetaminophen, an aspirin-free drug found in pain relievers such as Tylenol,does its job. Researchers at BYU believe COX-3 may be the enzyme the drugattacks to relieve pain.

"The study did begin with a study aimed at developing better nonsteroidalanti-inflammatory drugs for dogs (which is not yet published)," saysSimmons.

"What we're doing next - what I think is very important - is thatwe have to figure out what is going on in humans. There are some differencesin humans that apparently now are ironclad that have to be surmounted tofind out exactly how COX-3 is being expressed in humans.

Understanding pain

The birth of more effective pain relievers hinges on scientific understandingof the root cause of pain.

That in mind, Simmons says he and colleagues "are enlisting theaid" of the pharmaceutical industry to appropriately convert this discoveryinto new means of relief for people suffering from pain and fever.

Just over 30 years ago, scientists discovered that aspirin is activatedby restraining an enzyme called COX. In 1991, Simmons' lab discovered notone, but two COX enzymes. COX-2 was identified as being responsible forpain, fever and inflammation, while COX-1 conversely protected the gastrointestinaltract.

A new generation of pain and inflammation relievers called COX-2 inhibitorswas born, with the advent of such products as Celebrex and Vioxx. Thesenew drugs are effective because, although they neutralize COX-2 and itsnegative effects, they ignore COX-1, sparing chronic pain sufferers thedisabling stomach ulcers caused by aspirin-like drugs, known collectivelyas non-steroidal anti-inflammatory drugs (NSAIDs).

Acetaminophen, not an NSAID, is a very poor inhibitor of COX-1 or COX-2.

"Since the discovery of COX-2, we have learned an enormous amountabout how aspirin drugs work," says Simmons. "Going beyond theparadigm of COX-1 and COX-2 and asking whether there is any more complexityto the story has been difficult. For us, this is a good start."

Added bonus

In addition to the COX-3 discovery, researchers report the discoveryof two proteins, which he calls partial COX-1 or PCOX-1 proteins, whichappear to be related to the COX enzymes and are abundant in the canine brain,but whose functions are not yet known.

Ongoing research will analyze how the enzymes are inhibited and whatthey produce, says Simmons.

Assisting Simmons on the COX-3 research were biochemistry professor TerryElton; postdoctoral fellow and primary author N.V. Chandrasekharan; graduatestudents Hu Dai and K. Lamar Turepu Roos; and two undergraduates.

Coming soon

Research on NSAIDs' application in dogs may be published by early 2003in a veterinary journal, according to Simmons.

The original study on dogs was funded by an unrestricted, no-strings-attachedgift from Fort Dodge Animal Health, says Simmons, who adds he is not awareof how the data may be used.

The BYU study on COX-3 is available by contacting Jill Locantore at (202)334-1310 or jlocantore@nas.edu.