Understanding of Cystic Fibrosis Leads to Novel Findings about Drug-Induced Diarrhea
Research by Anjaparavanda Naren, PhD, into the underlying mechanisms of cystic fibrosis – a disease marked by impaired fluid secretions in the lung – is providing insights into why 7 percent of patients develop diarrhea as an adverse effect of certain prescription drugs.
Naren is the Thomas Boat Chair in Cystic Fibrosis Research and co-director, Cystic Fibrosis Research Center. He and a pulmonary medicine research team that included Chang Suk Moon, PhD, Kavisha Arora, PhD, and Sunitha Yarlagadda have identified an interplay between multidrug resistance protein 4 (MRP4) and the cystic fibrosis transmembrane conduct regulator (CFTR), a chloride channel on epithelial cells that retains and releases fluids. In cystic fibrosis, the channel underperforms, keeping fluids in the lungs; in diarrhea, the channel over-performs and releases fluids into the intestines and bowel.
“Until now, we did not have a good model system to study intestinal biopsies, because the tissue samples are so small,” Naren explains. His team deployed stem-cell technologies to create intestinal organoids, called “enteroids,” from tissue biopsies from mice. The enteroids were exposed in the lab to two drugs and monitored for excessive secretions – the symptoms of diarrhea. The enteroids also were monitored to determine how they responded to anti-diarrhea treatments.
The study in the May 1, 2015, Journal of Biological Chemistry involved irinotecan (a colon cancer drug) and AZT, an antiviral drug for HIV/AIDS. The drugs inhibited MRP4, producing compartmentalized accumulation of cAMP (3'-5'-cyclic adenosine monophosphate) in close proximity to the CFTR, activating the channel function and causing excessive fluid secretion and diarrhea.
“Our findings have broad implications and may help to identify therapeutic targets for ameliorating medication-induced diarrheas,” Naren says. “Enteroids allow us to use stem-cell techniques to develop a better index of chloride channel function, giving us the kinds of tools to move into personalized medicine.”
