New understanding of COX-1 and COX-2 enzymes could revise classification of pain meds

Queen's study shows enzyme 'hook up' in COX-2 inhibited mice

COX-1 and COX-2 enzymes may be blocked by pain medications such as Advil and Vioxx in a more complex manner than was previously understood, a Queen's University study has found.

"The results of the study have potential implications for how we classify the commonly used anti-inflammatory and pain drugs for aches, pains, and fever," says Colin Funk, a professor of Biochemistry and Physiology at Queen's and Canada Research Chair in Molecular, Cellular and Physiologiocal Medicine.

Published on-line in Nature Medicine, the study was conducted in collaboration with University of Pennsylvania researchers.

The study was initiated to explore the biochemistry associated with COX-2 inhibitors such as Vioxx, Bextra and Celebrex, which are now associated with an increased incidence of heart attack and stroke. Researchers looked at mice that were genetically modified so that their COX-2 was inhibited to create a physiology in mice that roughly mimics that of users of COX-2 inhibitors. They found that the COX-1 enzymes in the mice "hooked up" in an unanticipated way with their remaining COX-2 enzymes creating what is called a new heterodimer.

Dr. Funk's co-researcher, Queen's biochemist Robert Campbell, has developed a computer model to show how the COX-1/COX-2 molecules can associate.

"It's possible the COX-2 inhibitor medications may affect the resulting new enzyme which is a mix of COX-1 and COX-2," says Dr. Funk.

This effect is being further explored by scientists and may lead to a broadened understanding of the biochemistry of common pain medications. It is now pointing toward possible alternatives to drugs like Vioxx and Celebrex, says Dr. Funk.

A study published April 13 by The Journal of Clinical Investigation (JCI) by the same research team found that new types of anti-inflammatory drugs may reduce COX-2 cardiovascular problems. That study was conducted after this one and incorporated the genetically modified mice created in this study.

The JCI study found a drug target that might substitute for COX-2: an enzyme called microsomal prostaglandin E synthase (mPGES)-1. The researchers showed that this drug did not predispose the animals to thrombosis or elevate blood pressure.

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PLEASE NOTE: PDF copies of the study are available upon request

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