Bálint Tél MD 1, 2; Júlia Nám 2; Zoltán Kiss 1, 3; Péter Hegyi 3, 4; Gábor Veres 5; Petra Pallagi 2
1 Semmelweis University, 1st Department of Paediatrics, Budapest, Hungary
2 University of Szeged, First Department of Medicine, Szeged, Hungary
3 MTA-SE , Pediatrics and Nephrology Research Group , Budapest , Hungary.
4 University of Pécs, Medical School, Institute for Translational Medicine, Pécs, Hungary
5 University of Debrecen, Paediatric InstituteClinic, Debrecen, Hungary
Introduction and aims:
Numerous case-reports and observational studies suggest that several medication, such as azathioprine (AZA) and 5-aminosalicylic acid (5-ASA, mesalamine), can induce acute pancreatitis. The
important role of pancreatic ducts in the pathomechanism of acute pancreatitis has been highlighted
recently. Pancreatic ductal functions are essential for the homeostasis and integrity of the pancreas. Toxic
factors, such as alcohol or bile acids, can impair the ductal bicarbonate (HCO3-) secretion that can ultimately
lead to pancreatic injury. Our knowledge about pancreatic ductal functions in drug induced pancreatitis is,
however, limited. Since medications can also act as toxic factors, we wanted to investigate what effects do
AZA and 5-ASA have on pancreatic ductal functions and HCO3- secretion.
C57BL/6 mice were fed daily with 15 and 150 mg/kg AZA, as well as 50 and 500 mg/kg 5-ASA by gastric
feeding needle for one and four weeks. Mice were then euthanized and pancreatic ductal segments were
isolated with microdissection technique. Isolated pancreatic ducts were transferred to perfusion chambers
and were loaded with a pH sensitive fluorescent dye (BCECF-AM). Intracellular pH and rate of HCO3-secretion was determined using ratio microfluorimetry. Pancreatic ducts from non-treated animals were also
isolated and HCO3- secretion was assessed under normal conditions and during acute perfusion with
different solutions containing AZA and 5-ASA.
Acute perfusion of isolated pancreatic ductal fragments even with 1 μg/ml 5ASA or AZA caused significant
changes in ductal HCO3- secretion rates. When exposed to 10 and 100 μg/ml of 5-ASA ductal HCO3-
secretion rates were significantly lower as well. Perfusion with 10 and 100 μg/ml AZA also significantly
reduced ductal HCO3- secretion rates. Per os treatment with AZA for both one and four weeks impaired the
ductal HCO3- secretion rates. Ductal HCO3- secretion was also disturbed after one and four weeks of per os
treatment with 5-ASA.
Azathioprine and mesalamine can impair ductal bicarbonate secretion under acute exposure at several concentrations. Per os treatment for a longer timeperiod with both drugs can also
reduce pancreatic ductal functions. This effect might explain the relatively high number of acute pancreatitis
cases in patients treated with these medications. To better understand the exact molecular mechanisms,
further investigations are needed.
This study was supported by OTKA, MTA and ÚNKP
Doctoral School: Clinical Medicine
Program: Prevention of Chronic Diseases in Childhood
Supervisor: Gábor Veres