Study: Watch Out for Prescription-Level NSAIDs

By Jane Farrell

Three widely used drugs, known as nonsteroidal anti-inflammatory drugs, or NSAIDs, alter the activity of enzymes within cell membranes and could lead to unwanted side effects.

Those side effects could be the results of taking the drugs for a long period of time and/or at a higher-than-approved dosage level.

The NSAIDS, sold over the counter as aspirin, ibuprofen and naproxen, would have the effects primarily at prescription levels.

But, the Johns Hopkins researchers say, the good news is that their work provides the basis for a test that drug developers can use to avoid the alteration of activity of the enzymes within cell membranes.
The findings were published in the journal Cell Reports.

“When drug designers think about possible sources of side effects, they tend to think about which proteins are similar to the protein they are targeting, and they make sure that the former are not affected by the drug,” says Sinisa Urban, Ph.D., an associate professor of molecular biology and genetics at the Johns Hopkins University School of Medicine. “But our group has found that drugs that affect the cell membrane can alter the activity of proteins that are totally unrelated to the target.”

Urban and fellow invetigators focused on the activities of a group of enzymes known as rhomboid proteases. These enzymes cut protein like a scissors. Because different proteins are linked to different illnesses, such as malaria or Parkinson’s disease, the cutting of the proteins may affect a person’s health in differing ways. With the NSAIDs, the enzymes started cutting proteins they don’t’ normally cut.

Aware that many drugs end up in the cell membrane, Urban assessed the effect of certain drugs on rhomboid proteases’ ability to recognize their normal clients.

“It’s possible that some of the side effects of NSAIDs are caused by their effect on the membrane and its enzymes,” says Urban. “Our results are also a caution to drug developers trying to target new drugs to the membrane or hoping to increase the duration or dosage of already approved drugs. Throwing off the balance of the membrane has consequences.”