Zebrafish: Drug discovery of a different stripe holds promise in COX research

(Philadelphia, PA) Researchers at the University of Pennsylvania School of Medicine have discovered that zebrafish produce enzymes analogous to the two human cyclooxygenase (COX) enzymes COX-1 and 2 proteins that have a role in a variety of ailments including cardiovascular disease, some types of cancer, and arthritis. Furthermore, drugs that target the COX enzymes, nonsteroidal anti-inflammatory drugs (NSAIDs) and selective inhibitors of COX-2, seem to act in a manner similar to humans.

"We have learned a great deal about how the COX enzymes and their inhibitors work from mouse models of COX gene inactivation," said Garret A. FitzGerald, MD, Chair of the Department of Pharmacology and director of the Center for Experimental Therapeutics at Penn. " However, these systems have their limitations. The zebrafish promises to play a complementary role in which both biology and the role of drugs can be investigated."

Traditionally zebrafish have been useful in searching for gene mutations induced by exposure to toxic chemicals, which coincide with abnormalities of development. Such an approach is termed "forward genetics."

The Penn paper, detailed in this week's print edition of the Proceedings of the National Academy of Sciences, is an early example of the use of zebrafish for "reverse genetics." A particular set of genes in this case, the COXs are sought out and their function is uncovered by manipulating their action in zebrafish. The COX enzymes produce prostaglandins, fatty acids that perform a number of hormone-like tasks. Prostaglandins alter the activities of the cells near and around where they are made. They also cause inflammation and can regulate blood flow to some organs, transport across cell membranes, and transmissions between neurons.

The COX proteins are encoded by separate genes on separate chromosomes and, likewise, have two separate but interdependent functions. COX-1 is responsible for the "day-to-day" production

Contact: Greg Lester
University of Pennsylvania School of Medicine

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