21 Jul 1998: Shellfish Toxin Study Provides Possible Clue to Cystic Fibrosis Therapy

Scientists studying how a toxin in shellfish causes diarrhea in humans today reported that they have discovered a mechanism that may help treat cystic fibrosis.

A consortium of seven scientists from the National Institute of Environmental Health Sciences and the Universities of Chicago, Cincinnati and Manchester (UK) described their findings in the Aug. 1 issue of the Journal of Physiology (http://jp.physoc.org/) . The toxin, okadaic acid, is produced by algae upon which shellfish feed. Although not usually life-threatening, it is a recurrent economic plague on the shellfish industry, particularly in Europe and Japan.

The symptoms of cystic fibrosis arise from there being a genetic block of a major pathway of salt and fluid secretion. The patients' bodies do have another pathway of salt and fluid secretion -- and for many years scientists have sought to develop drugs to increase the activity of this alternative secretory pathway.

Unfortunately, the body normally needs to protect itself from excessive loss of salt and fluid. So cells produce a substance that inhibits the very pathway of fluid secretion that the drugs are designed to increase.

But the new shellfish poisoning study shows that the toxin okadaic acid defeats this built-in fluid conservation mechanism through an interaction with a special class of enzymes known as protein phosphatases.

In the shellfish poisoning, okadaic acid leads to a loss of intestinal salt and fluid, watery diarrhea, cramps and discomfort. Stephen Shears, Ph.D., of NIEHS, proposes that a drug be found to use this same mechanism to stimulate fluid to flow from the cells affected by cystic fibrosis, but without the toxic side effects. The fluid could loosen the mucus that accumulates in the lungs and gut and predisposes people with cystic fibrosis to severe bacterial infections and early death.

Dr. Shears said, "Our group of cooperating scientists obviously believes it is important to learn more about how a shellfish toxin causes diarrhea. That's significant in itself.

"But you can see in this example," Dr. Shears added, "how one scientific discovery can lead to another: A new drug can be based upon inhibiting the protein phosphatases that slow fluid output in the lungs of cystic fibrosis patients. The study of an important environmental toxin may reap unexpected benefits for the treatment of a common and debilitating genetic disease."

The other researchers on the cooperative study are Weiwen Xie, B.S., of the Department of Neurology at the University of Chicago; Kevin R.H. Solomons, Ph.D., and Sally Freeman, Ph.D., of the School of Pharmacy and Pharmaceutical Sciences at the University of Manchester; Marcia A. Kaetzel, Ph.D., of the College of Medicine, University of Cincinnati; Karol S. Bruzik, Ph.D., of the College of Pharmacy at the University of Illinois, Chicago; Deborah J. Nelson, Ph.D., University of Chicago.