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Event: 1722

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Increased blood CCK level

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Increased blood CCK level

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
TI-induced AC tumors KeyEvent Arthur Author (send email) Under development: Not open for comment. Do not cite Under Development


This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Macaca fascicularis Macaca fascicularis High NCBI
Rattus norvegicus Rattus norvegicus High NCBI
Mus musculus Mus musculus High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
All life stages High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Mixed High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Pancreatic exocrine secretion is controlled by multiple mechanisms [Caron J et al, 2017; Wang BJ and Cui ZJ, 2007; Wang Y et al, 2011], many of which are mediated by CCK secreted by CCK-producing I cells lining the mucosa of the small intestine [Singer MV and Niebergall-Roth E, 2009; Rehfeld JF, 2017]. CCK is also synthesized in cerebral neurons and expressed in several endocrine and certain other cells, and they are involved in many functions other than pancreatic exocrine secretion, including gall bladder contraction, gut motility, and satiety [Rehfeld JF, 2017].

CCK is initially synthesized as a peptide prohormone comprising 150 amino acids, which is processed into active CCK by prohormone convertases specific to the cell type and species [Rehfeld JF et al, 2003; Wang BJ and Cui ZJ, 2007]. CCKs exist as several isoforms that differ due to post-translational modifications, although the C-terminal amino acid sequences are conserved among these isoforms [Rehfeld JF et al, 2001; Rehfeld JF, 2017].

CCK release is stimulated mainly by gastric contents containing fatty acids and amino acids transported into the small intestine. The factors in gastric chyme that stimulate CCK release differ among species, with fats, fatty acids, proteins, and amino acids being the key players in humans, fatty acids and amino acids in canines, and digested/undigested proteins in rats [Wang BJ and Cui ZJ, 2007; Caron J et al, 2017]. These factors stimulate intestinal mucosal I cells to release CCK into the blood either directly via specific receptors such as calcium-sensing receptors and the G protein-coupled receptor GPR93 or indirectly via luminal CCK-releasing factors (LCRFs) [Caron J et al, 2017]. LCRFs are released from intestinal mucosal cells in response to amino acids and fatty acids in humans [Liddle RA, 1997; Liddle RA, 2000] ; however, the peptides mediate negative feedback regulation of CCK release via CCK degradation by pancreatic proteases [Wang BJ and Cui ZJ, 2007].

In addition to the negative feedback regulation of CCK release in rodents, CCK release is stimulated by monitor peptide (MP), a pancreatic soluble trypsin inhibitor (PSTI) secreted into the upper intestine from pancreatic acinar cells [Wang BJ and Cui ZJ, 2007]. MP, which is trypsin-sensitive, stimulates intestinal I cells to release CCK via positive feedback regulation, in that the resulting increased CCK level stimulates the secretion of MP together with other pancreatic enzymes [Liddle RA, 1995; Wang BJ and Cui ZJ, 2007; Miyasaka K and Funakoshi A, 1998]

When trypsin is inhibited in rodents, trypsin-sensitive MP-induced CCK release is overstimulated due to positive feedback regulation of CCK release by trypsin.

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Plasma was first extracted on octadecylsilyl silica columns, and the CCK concentration was measured in the resulting extracts, based on the ability of the extracts to stimulate amylase release from isolated rat pancreatic acini [Liddle RA et al, 1984].

The STC-1 cell line, which is derived from murine enteroendocrine tumor cells, secretes several enteroendocrine hormones including CCK, GLP-1, and GLP-2 in response to many different stimulants such as monosaccharides, aromatic amino acids, peptidomimetic compounds, and bitter tastants [Wang BJ and Cui ZJ, 2007].

CCK release from STC-1 cells or intestinal cell preparation were measured by sensitive and specific radioimmunoassay, which recognizes biologically active forms of CCK [Wang Y et al, 2002; Wang Y et al, 2011].

In order to assess the effects of protein hydrolysates on CCK release from enteroendocrine cells, each of protein hydrolysates and STC-1 cells were incubated and CCK release is measured by ELISA [Foltz M et al, 2008].

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

There are species differences in the regulation of CCK release.

Fats, fatty acids, proteins, and amino acids stimulate CCK release in humans, and fatty acids and amino acids are the key factors regulating CCK release in dogs. These factors stimulate intestinal I cells to release CCK either directly via cell surface receptors such as Ca-sensing receptors and the G protein-coupled receptor GPR93 or indirectly via LCRFs [Caron J et al, 2017]. Amino acids directly stimulate LCRF release from small intestinal mucosal cells in humans [Wang BJ and Cui ZJ, 2007].

On the other hand, in rodents, trypsin-mediated negative and positive feedback regulation loops involved in CCK release have been identified; the former is mediated by LCRF secreted from intestinal mucosal cells and the latter via MP secreted from pancreatic acinar cells [Liddle RA, 1995; Wang BJ and Cui ZJ, 2007; Miyasaka K and Funakoshi A, 1998]. This mechanism of CCK release regulation is plausible in rodents, because of their diet of wild legumes and cereal grains, which contain trypsin inhibitors, and the short digestion time in the stomach.

Multiple isoforms of CCKs (e.g., CCK-83, -58, -39, -33, -22, -8, and others) have been identified, and their expression differs among species (humans express CCK-33, -22, and -58; dogs express CCK-58; cats express CCK-8, -33, and -58; pigs express CCK-22, -58, -3, and -8; rabbits express CCK-22 and -8; and rats express CCK-58). All CCK isoforms contain a highly conserved region of amino acids and serve as ligands for CCK1 receptors [Wang BJ and Cui ZJ, 2007; Rehfeld JF, 2017].


List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide ( (OECD, 2015). More help

 1.    Caron J, Domenger D, Dhulster P, Ravallec R, Cudennec B: Protein digestion-derived peptides and the peripheral regulation of food intake. Front Endocrinol (Lausanne) 8:85,2017

 2.    Foltz M, Ansems P, Schwarz J, Tasker MC, Lourbakos A, Gerhardt CC: Protein hydrolysates induce CCK release from enteroendocrine cells and act as partial agonists of the CCK1 receptor. J Agric Food Chem 56:837-843,2008

 3.    Goke B, Printz H, Koop I, Rausch U, Richter G, Arnold R, Adler G: Endogenous CCK release and pancreatic growth in rats after feeding a proteinase inhibitor (camostate). Pancreas 1:509-515,1986

 4.    Liddle RA, Goldfine ID, Williams JA: Bioassay of plasma cholecystokinin in rats: effects of food, trypsin inhibitor, and alcohol. Gastroenterology 87:542-549,1984

 5.    Liddle RA: Regulation of cholecystokinin secretion by intraluminal releasing factors. Am J Physiol 269:G319-27,1995

 6.    Liddle RA: Cholecystokinin cells. Annu Rev Physiol 59:221-242,1997

 7.    Liddle RA: Regulation of cholecystokinin secretion in humans. J Gastroenterol 35:181-187,2000

 8.    Miyasaka K, Funakoshi A: Luminal feedback regulation, monitor peptide, CCK-releasing peptide, and CCK receptors. Pancreas 16:277-283,1998

 9.    Rehfeld JF, Sun G, Christensen T, Hillingso JG: The predominant cholecystokinin in human plasma and intestine is cholecystokinin-33. J Clin Endocrinol Metab 86:251-258,2001

10.    Rehfeld JF, Bungaard JR, Friis-Hansen L, Goetze JP: On the tissue-specific processing of procholecystokinin in the brain and gut--a short review. J Physiol Pharmacol 54 Suppl 4:73-79,2003

11.    Rehfeld JF: Cholecystokinin-From Local Gut Hormone to Ubiquitous Messenger. Front Endocrinol (Lausanne) 8:47,2017

12.    Singer MV, Niebergall-Roth E: Secretion from acinar cells of the exocrine pancreas: role of enteropancreatic reflexes and cholecystokinin. Cell Biol Int 33:1-9,2009

13.    Wang BJ, Cui ZJ: How does cholecystokinin stimulate exocrine pancreatic secretion? From birds, rodents, to humans. Am J Physiol Regul Integr Comp Physiol 292:R666-78,2007

14.    Wang Y, Prpic V, Green GM, Reeve JR Jr, Liddle RA: Luminal CCK-releasing factor stimulates CCK release from human intestinal endocrine and STC-1 cells. Am J Physiol Gastrointest Liver Physiol 282:G16-22,2002

15.    Wang Y, Chandra R, Samsa LA, Gooch B, Fee BE, Cook JM, Vigna SR, Grant AO, Liddle RA: Amino acids stimulate cholecystokinin release through the Ca2+-sensing receptor. Am J Physiol Gastrointest Liver Physiol 300:G528-537,2011