Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|TI-induced AC tumors||AdverseOutcome|
|Homo sapiens||Homo sapiens||Moderate||NCBI|
|Macaca fascicularis||Macaca fascicularis||Moderate||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
|Mus musculus||Mus musculus||Moderate||NCBI|
|All life stages||High|
Key Event Description
Several reports have shown that increased blood CCK levels directly stimulate acinar cell proliferation via CCK1 receptors in rats as follows:
In rats with a sustained increase in the CCK level due to treatment with a CCK1 receptor agonist (CCK-8), acinar cell proliferation and pancreatic hypertrophy were induced [Folsch UR et al, 1978; Povoski SP et al, 1994]. Endogenous and exogenous increases in blood CCK levels induced pancreatic hypertrophy due to the direct action of CCK on acinar cells [Yamamoto M et al, 2003]. Repeated administration of the CCK1 receptor agonist GI181771X to rats and mice resulted in pancreatic injury, hypertrophy and diffuse/focal hyperplasia of acinar cells, and zymogen degranulation depending on the dose and dosing period [Myer JR et al, 2014].
Administration of the trypsin inhibitor A8947 to rats increased pancreatic weight; however, infusion of the selective CCK1 receptor antagonist MK-329 using an osmotic minipump completely diminished this effect of A8947 on pancreatic weight [Obourn JD et al, 1997].
These results indicate that CCK directly stimulates pancreatic acinar cell proliferation via CCK1 receptors, and trypsin inhibition enhances acinar cell proliferation due to an increased plasma level of CCK.
How It Is Measured or Detected
Pancreatic acinar cell proliferation is evaluated based on measurements of pancreatic weight and DNA and RNA levels [Folsch UR et al, 1978; Povoski SP et al, 1994; Tashiro M et al, 2004], as well as histopathological examination [Povoski SP et al, 1994]. In these experiment, pancreatic weight, protein content, RNA content, DNA content, protein-DNA ratio, RNA-DNA ratio, pancreatic area per nucleus, and number of mitoses per 10,000 acinar cells could be determined. Among such parameters, Increased DNA content and number of mitoses per 10,000 acinar cells are indicative of acinar cell hyperplasia, and the others suggest pancreatic or acinar cell hypertrophy and increased pancreatic protein synthesis.
Domain of Applicability
In monkeys receiving repeated dosing of the CCK1 receptor agonist GI181771X for up to 52 weeks, no hypertrophy or histopathological changes of the pancreas were observed, but these results differed from those of rats [Myer JR et al, 2014]. In humans, obese patients treated with GI181771X for 24 weeks showed no abnormal changes in the pancreas by ultrasonography or MRI [Jordan J et al, 2008]. On the other hand, oral ingestion of raw soya flour, which contains trypsin inhibitors, increased the release of CCK in humans [Calam J et al, 1987]. In addition, some epidemiological studies reported that the incidence of pancreatic tumors in humans administered high levels of protease inhibitors was decreased [Messina M and Messina V, 1991; Miller RV, 1978]. These results suggest no relevance between pancreatic growth/tumor development and CCK-agonist treatment in humans or non-human primates.
As indicated above, the effects of CCK on acinar cell proliferation differ between rodents and humans. In rodents, proliferation of pancreatic acinar cells is regulated directly via CCK1 receptors expressed on their surfaces. However, in humans, CCK1 receptor density on the surface of pancreatic acinar cells is low, and exocrine secretion is innervated by vagal afferent nerves, with little effect on acinar cell proliferation.
Regulatory Significance of the Adverse Outcome
1. Calam J, Bojarski JC, Springer CJ: Raw soya-bean flour increases cholecystokinin release in man. Br J Nutr 58:175-179,1987
2. Folsch UR, Winckler K, Wormsley KG: Influence of repeated administration of cholecystokinin and secretin on the pancreas of the rat. Scand J Gastroenterol 13:663-671,1978
3. Jordan J, Greenway FL, Leiter LA, Li Z, Jacobson P, Murphy K, Hill J, Kler L, Aftring RP: Stimulation of cholecystokinin-A receptors with GI181771X does not cause weight loss in overweight or obese patients. Clin Pharmacol Ther 83:281-287,2008
4. Messina M, Messina V: Increasing use of soyfoods and their potential role in cancer prevention. J Am Diet Assoc 91:836-840,1991
5. Miller RV: Epidemiology. Alan R. Liss, New York (pp) 39-57,1978
6. Myer JR, Romach EH, Elangbam CS: Species- and dose-specific pancreatic responses and progression in single- and repeat-dose studies with GI181771X: a novel cholecystokinin 1 receptor agonist in mice, rats, and monkeys. Toxicol Pathol 42:260-274,2014
7. Obourn JD, Frame SR, Chiu T, Solomon TE, Cook JC: Evidence that A8947 enhances pancreas growth via a trypsin inhibitor mechanism. Toxicol Appl Pharmacol 146:116-126,1997
8. Povoski SP, Zhou W, Longnecker DS, Jensen RT, Mantey SA, Bell RH Jr: Stimulation of in vivo pancreatic growth in the rat is mediated specifically by way of cholecystokinin-A receptors. Gastroenterology 107:1135-1146,1994
9. Tashiro M, Samuelson LC, Liddle RA, Williams JA: Calcineurin mediates pancreatic growth in protease inhibitor-treated mice. Am J Physiol Gastrointest Liver Physiol 286:G784-790,2004
10. Yamamoto M, Otani M, Jia DM, Fukumitsu K, Yoshikawa H, Akiyama T, Otsuki M: Differential mechanism and site of action of CCK on the pancreatic secretion and growth in rats. Am J Physiol Gastrointest Liver Physiol 285:G681-687,2003