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Relationship: 2029

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Increased monitor peptide leads to Increased blood CCK level

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Trypsin inhibition leading to pancreatic acinar cell tumors adjacent High Moderate Arthur Author (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Select one or more structured terms that help to define the biological applicability domain of the KER. In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens Low NCBI
Macaca fascicularis Macaca fascicularis Low NCBI
Rattus norvegicus Rattus norvegicus High NCBI
Mus musculus Mus musculus High NCBI

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Sex Evidence
Mixed High

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
Term Evidence
All life stages High

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help
 

Pancreatic exocrine secretion is regulated mainly by cholecystokinin (CCK) via multiple mechanisms. In the digestive system, CCK is released by I cells located in the duodenal mucosa of the small intestine. CCK release is at least in part under negative or positive feedback regulation mediated by trypsin-sensitive CCK-releasing peptides.

In rats, CCK release from I cells is regulated actively by monitor peptide (MP) secreted from pancreatic acinar cells in the presence of nutritional protein in the duodenum [Graf R, 2006].

In the empty intestine, secreted MP binds to trypsin and thus maintained at low intestinal levels; in this situation, CCK release is suppressed. Once the gastric contents are transported to the small intestine, secretion of pancreatic juice including trypsin and MP is stimulated, where trypsin is used for digestion, and the level of free MP is subsequently increased. The increased free MP level stimulates CCK release from I cells via MP receptors, and the resulting increase in CCK stimulates pancreatic exocrine secretion including MP. The resulting increased level of MP directly stimulates I cells to release CCK further; this positive feedback regulation might be continued as long as duodenal contents remain to consume trypsin for proteolysis.

Meanwhile, soon after nutritional protein is digested, free MP and excessive trypsin binds together to be subsequently degraded followed by decreases in blood level of CCK and pancreatic secretion. However, after ingestion of trypsin inhibitors, the intestinal concentration of MP is increased continuously with positive feedback manner due to inhibition of its degradation by trypsin.

On the other hand, in mammalian species including rodents, negative feedback regulation of trypsin secretion is mediated by trypsin-sensitive luminal CCK-releasing peptide (LCRF) secreted from the mucosa of the upper intestine into the intestinal lumen in response to dietary components such as amino acids and peptides. LCRF directly stimulates I cells to secrete CCK, with a resulting increase in trypsin secretion from pancreatic acinar cells, and trypsin then degrades LCRF, indicating negative feedback regulation of trypsin-mediated CCK release.

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help

TBD

Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured (see page 40 of the User Handbook for further information).   More help

Regulation of pancreatic secretion

Pancreatic exocrine secretion is controlled mainly by the gastrointestinal hormone cholecystokinin (CCK), which is secreted by CCK-producing I cells located in the mucosa of the small intestine. Multiple mechanisms are involved in the stimulation of CCK release [Wang BJ and Cui ZJ, 2007; Caron J et al, 2017].

Regulation of CCK release mediated by monitor peptide (MP) in rats

In rats, CCK release from I cells in the duodenal mucosa of the small intestine is regulated actively by MP [Miyasaka K et al, 1989a; Fushiki T et al, 1989; Iwai K et al, 1988; Miyasaka K and Funakoshi A, 1998], which consists of 61 amino acids with a molecular weight of approximately 6000. It was first purified from rat pancreatic juice, and its amino acid sequence was subsequently determined [Iwai K et al, 1987].

In the empty intestine, secreted MP is bound to trypsin and thus free MP is maintained at a low level in the intestine; in this situation, CCK release is suppressed. However, after the gastric contents are transported to the small intestine, proteases are postulated to be used for protein hydrolysis, allowing the amount of free MP to increase [Iwai K et al, 1988; Liddle RA, 1995; Miyasaka K and Funakoshi A, 1998; Graf R, 2006]. The increased MP stimulates mucosal I cells to release CCK via their surface MP receptors, stimulating pancreatic exocrine secretion [Liddle RA et al, 1992; Guan D et al, 1990; Cuber JC et al, 1990]. MP binds to the surface of CCK-immunoreactive mucosal cells in the small intestine [Yamanishi R et al, 1993a; Yamanishi R et al, 1993b]. After proteolysis of the intestinal contents, the luminal level of free trypsin is increased, which causes the luminal MP level to return to a low level, followed by a decrease in CCK release [Liddle RA, 1995; Miyasaka K and Funakoshi A, 1998; Graf R, 2006].

Another role of MP as a pancreatic secretory trypsin inhibitor (TI)

Similar to other pancreatic soluble TIs, MP forms complexes with trypsin in the empty intestine to prevent auto-injury by trypsin [Lin YZ et al, 1990; Voet D and Voet JG, 1995]. Once TI is ingested, TI–trypsin complexes are formed, and the intestinal level of free MP is increased to stimulate CCK release [Yamanishi R et al, 1993b], increasing the blood CCK level even on an empty intestine. TIs other than MP show no effect on CCK release [Miyasaka K, 1989a;              Tsuzuki S, 1991].

Effects of TIs on MP-mediated CCK release

In contrast, once TIs are ingested, the intestinal concentration of MP is increased due to inhibition of its binding with trypsin and degradation, and the increased MP directly stimulates I cells to release CCK into the blood. In turn, the increased CCK stimulates pancreatic acinar cells to secrete MP as well as pancreatic enzymes, and the secretion of MP further upregulates CCK release via a positive feedback mechanism, especially under trypsin inhibition [Wang BJ and Cui ZJ, 2007; Liddle RA, 1995; Miyasaka K and Funakoshi A, 1998; Liddle RA, 1995].

Some studies have reported that intraduodenal injection of MP stimulates CCK release in rats with external biliary and pancreatic fistulae [Miyasaka K et al, 1989a; Longnecker DS, 1987].

Raw soya flour containing TIs and protease inhibitors such as camostat directly inhibit trypsin activity, and rats treated with these agents showed an increased blood level of CCK [Liddle RA et al, 1984; Goke B et al, 1986; Calam J et al, 1987; Douglas BR et al, 1989; Cuber JC et al, 1990; Playford RJ et al, 1993; Obourn JD et al, 1997; Tashiro M et al, 2004; Komarnytsky S et al, 2011] . The mechanism underlying the increase in CCK release by TIs is thought to involve an increase in the intestinal MP level resulting from trypsin inhibition [Iwai K et al, 1988; Cuber JC et al, 1990; Miyasaka K et al, 1989a].

CCK

CCK is a peptide hormone secreted by I cells located in the mucosa of the small intestine, and it regulates pancreatic exocrine secretion. CCK is secreted as peptide prohormone consisting of 150 amino acids. Several CCK isoforms exist, composed of different numbers of amino acids due to post-transcriptional modifications, although the amino acid sequence of the C-terminal end is common among these isoforms [Rehfeld JF, 2017; Wang BJ and Cui ZJ, 2007].

In addition, MP receptors are thought to be expressed on I cells, based on the findings that MP binds to CCK-positive cells in the mucosa of the small intestine, and this binding is inhibited by TIs [Yamanishi R et al, 1993a; Yamanishi R et al, 1993b].

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

TBD

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help

MP at concentrations ranging from 3 x 10-12 to 3 x 10-8 M stimulated mucosal cells isolated from the rat duodenum to release CCK in a dose-dependent manner [Bouras EP et al, 1992].

MP at a concentration range of 2–12 µg/mL induced a dose-dependent transient increase in portal CCK-like immunoreactivity in isolated vascularly perfused rat duodeojejunum MP at 36 µg/mL showed lower CCK release [Cuber JC et al, 1990].

Time-scale
This sub-section should be used to provide information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help

MP stimulated CCK release from isolated mucosal cells from the rat duodenum, sorted CCK-positive rat intestinal mucosal cells, or isolated vascularly perfused rat duodenum/jejunum after or within several minutes from the incubation [Liddle RA et al, 1992; Bouras EP et al, 1992; Cuber JC et al, 1990].

Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help

In addition to by MP in rats, CCK release from duodenal I cells is stimulated by gastric contents containing fatty acids and amino acids, either directly by specific receptors such as Ca-sensing receptors and the G protein-coupled receptor GPR93 or indirectly by luminal CCK-releasing factors (LCRF) in rats and humans[Caron J et al, 2017]. In humans, LCRF is released from intestinal mucosal cells in response to amino acids and fatty acids, and the LCRF mediate negative feedback regulation of CCK release via LCRF degradation by trypsin [Wang BJ and Cui ZJ, 2007].

Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

In rodents, monitor peptide, a pancreatic secretory trypsin inhibitor, is secreted by pancreatic acinar cells along with trypsin and other digestive enzymes stimulated by CCK [Iwai K et al, 1988; Tsuzuki S et al, 1991]. Because MP binds tightly to trypsin [Voet D and Voet JG, 1995], trypsin inhibition increases the intraluminal concentration of MP in a positive feedback manner [Liddle RA et al, 1984; Wang BJ and Cui ZJ, 2007].

Meanwhile, in mammalian species including rodents, TIs might stimulate CCK release into the bloodstream via an increased luminal concentration of trypsin-sensitive CCK-releasing peptides secreted by duodenal mucosal cells [Miyasaka K et al, 1989c; Lu L et al, 1989; Guan D et al, 1990; Owyang C, 1994; Liddle RA, 1995; Spannagel AW et al, 1996; Herzig KH et al, 1996; Miyasaka K and Funakoshi A, 1998; Marchbank T et al, 1998; Li Y et al, 2000; Owyang C, 1999; Wang Y et al, 2002] . Increased blood level of CCK does not stimulate further secretion of LCRF different from the positive feedback regulation of CCK release by MP.

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

Monitor peptide and related peptides with trypsin inhibitory activity

Pancreatic secretory trypsin inhibitors (PSTIs) are found in the pancreatic juice of multiple mammalian species, including rodents and humans [Greene LJ et al, 1968; Pubols MH et al, 1974; Eddeland A and Ohlsson K, 1976; Kikuchi N et al, 1985]. Secreted PSTIs bind tightly to trypsin to protect against trypsin-induced auto-injury in the pancreas and intestinal tracts [Voet D and Voet JG, 1995].

In rats, two types of PSTIs have been isolated: monitor peptide (MP, also known as PSTI-I) and PSTI-II [Tsuzuki S et al, 1991; Tsuzuki S et al, 1992]. Both are similar in amino acid sequence; however, the former directly stimulates CCK release from intestinal I cells via their surface MP receptors, whereas the latter does not [Miyasaka K et al, 1989b; Yamanishi R et al, 1993a]. Human PSTIs do not directly stimulate CCK release from intestinal mucosal cells [Miyasaka K et al, 1989a]. PSTIs from other mammalian species including dogs and pigs might neither directly stimulate CCK release although no related reports are found.

Species differences in the mechanism of CCK release

Pancreatic exocrine secretion is controlled mainly by CCK released into the bloodstream from intestinal mucosal I cells of the small intestine in response to the gastric contents transported to the intestine [Singer MV and Niebergall-Roth E, 2009; Rehfeld JF, 2017]. Peptides released from gastrointestinal digestion, along with fatty acids, are the main stimuli of CCK release involving several direct and indirect pathways [Caron J et al, 2017].

In humans and canines, amino acids and fatty acids in the gastric contents transported to the small intestine play a major role in stimulating CCK release, which regulates pancreatic exocrine secretion, but MP is not involved in exocrine regulation [Wang BJ and Cui ZJ, 2007].

In rats, in contrast to other mammalian species, MP secreted by pancreatic acinar cells plays a major role in protein-stimulated CCK release [Iwai K et al, 1988; Fushiki T et al, 1989]. Ingestion of TIs increases the intestinal level of MP, especially after all nutrient protein is digested in the intestines, causing a subsequent increase in the blood level of CCK. Increased levels of CCK stimulate pancreatic exocrine secretion of proteins including MP, which in turn further increases the release of CCK. This positive feedback response associated with MP secretion might lead to continuously elevated plasma levels of CCK [Liddle RA, 1995].

Species differences in CCKs

Several isoforms of CCK, including CCK-83, -58, -39, -33, -22, and -8, have been identified, and there are species differences in CCK isoforms (e.g., CCK-33, -22 and -58 are expressed in humans, CCK-58 in dogs, CCK-8, -33 and -58 in cats, CCK-22, -58, -3 and -8 in pigs, CCK-22 and -8 in rabbits, and CCK-58 in rats). All of these CCK isoforms have a highly conserved region of amino acids, and all are ligands of CCK1 receptors [Wang BJ and Cui ZJ, 2007].

References

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

 1.    Bouras EP, Misukonis MA, Liddle RA: Role of calcium in monitor peptide-stimulated cholecystokinin release from perfused intestinal cells. Am J Physiol 262:G791-6,1992

 2.    Calam J, Bojarski JC, Springer CJ: Raw soya-bean flour increases cholecystokinin release in man. Br J Nutr 58:175-179,1987

 3.    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

 4.    Cuber JC, Bernard G, Fushiki T, Bernard C, Yamanishi R, Sugimoto E, Chayvialle JA: Luminal CCK-releasing factors in the isolated vascularly perfused rat duodenojejunum. Am J Physiol 259:G191-197,1990

 5.    Douglas BR, Woutersen RA, Jansen JB, de Jong AJ, Rovati LC, Lamers CB: Modulation by CR-1409 (lorglumide), a cholecystokinin receptor antagonist, of trypsin inhibitor-enhanced growth of azaserine-induced putative preneoplastic lesions in rat pancreas. Cancer Res 49:2438-2441,1989

 6.    Eddeland A, Ohlsson K: Purification of canine pancreatic secretory trypsin inhibitor and interaction in vitro with complexes of trypsin-alpha-macroglobulin. Scand J Clin Lab Invest 36:815-820,1976

 7.    Fukuda M, Fujiyama Y, Sasaki M, Andoh A, Bamba T, Fushiki T: Monitor peptide (rat pancreatic secretory trypsin inhibitor) directly stimulates the proliferation of the nontransformed intestinal epithelial cell line, IEC-6. Digestion 59:326-330,1998

 8.    Fushiki T, Kajiura H, Fukuoka S, Kido K, Semba T, Iwai K: Evidence for an intraluminal mediator in rat pancreatic enzyme secretion: reconstitution of the pancreatic response with dietary protein, trypsin and the monitor peptide. J Nutr 119:622-627,1989 9.    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

10.    Graf R, Bimmler D: Biochemistry and biology of SPINK-PSTI and monitor peptide. Endocrinol Metab Clin North Am 35:333-43, ix,2006

11.    Greene LJ, DiCarlo JJ, Sussman AJ, Bartelt DC: Two trypsin inhibitors from porcine pancreatic juice. J Biol Chem 243:1804-1815,1968

12.    Guan D, Ohta H, Tawil T, Liddle RA, Green GM: CCK-releasing activity of rat intestinal secretion: effect of atropine and comparison with monitor peptide. Pancreas 5:677-684,1990

13.    Herzig KH, Schon I, Tatemoto K, Ohe Y, Li Y, Folsch UR, Owyang C: Diazepam binding inhibitor is a potent cholecystokinin-releasing peptide in the intestine. Proc Natl Acad Sci U S A 93:7927-7932,1996

14.    Iwai K, Fukuoka S, Fushiki T, Tsujikawa M, Hirose M, Tsunasawa S, Sakiyama F: Purification and sequencing of a trypsin-sensitive cholecystokinin-releasing peptide from rat pancreatic juice. Its homology with pancreatic secretory trypsin inhibitor. J Biol Chem 262:8956-8959,1987

15     Iwai K, Fushiki T, Fukuoka S: Pancreatic enzyme secretion mediated by novel peptide: monitor peptide hypothesis. Pancreas 3:720-728,1988

16.    Kikuchi N, Nagata K, Yoshida N, Ogawa M: The multiplicity of human pancreatic secretory trypsin inhibitor. J Biochem 98:687-694,1985

17.    Komarnytsky S, Cook A, Raskin I: Potato protease inhibitors inhibit food intake and increase circulating cholecystokinin levels by a trypsin-dependent mechanism. Int J Obes (Lond) 35:236-243,2011

18.    Li Y, Hao Y, Owyang C: Diazepam-binding inhibitor mediates feedback regulation of pancreatic secretion and postprandial release of cholecystokinin. J Clin Invest 105:351-359,2000

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

20.    Liddle RA, Misukonis MA, Pacy L, Balber AE: Cholecystokinin cells purified by fluorescence-activated cell sorting respond to monitor peptide with an increase in intracellular calcium. Proc Natl Acad Sci U S A 89:5147-5151,1992

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

22.    Lin YZ, Isaac DD, Tam JP: Synthesis and properties of cholecystokinin-releasing peptide (monitor peptide), a 61-residue trypsin inhibitor. Int J Pept Protein Res 36:433-439,1990

23.    Longnecker DS: Interface between adaptive and neoplastic growth in the pancreas. Gut 28 Suppl:253-258,1987

24.    Lu L, Louie D, Owyang C: A cholecystokinin releasing peptide mediates feedback regulation of pancreatic secretion. Am J Physiol 256:G430-435,1989

25.    Marchbank T, Freeman TC, Playford RJ: Human pancreatic secretory trypsin inhibitor. Distribution, actions and possible role in mucosal integrity and repair. Digestion 59:167-174,1998

26.    Miyasaka K, Nakamura R, Funakoshi A, Kitani K: Stimulatory effect of monitor peptide and human pancreatic secretory trypsin inhibitor on pancreatic secretion and cholecystokinin release in conscious rats. Pancreas 4:139-144,1989a

27.    Miyasaka K, Funakoshi A, Nakamura R, Kitani K, Uda K, Murata A, Ogawa M: Differences in stimulatory effects between rat pancreatic secretory trypsin inhibitor-61 and -56 on rat pancreas. Jpn J Physiol 39:891-899,1989b

28.    Miyasaka K, Guan DF, Liddle RA, Green GM: Feedback regulation by trypsin: evidence for intraluminal CCK-releasing peptide. Am J Physiol 257:G175-81,1989c

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

30.    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

31.    Owyang C: Negative feedback control of exocrine pancreatic secretion: role of cholecystokinin and cholinergic pathway. J Nutr 124:1321S-1326S,1994

32.    Owyang C: Discovery of a cholecystokinin-releasing peptide: biochemical characterization and physiological implications. Chin J Physiol 42:113-120,1999

33.    Playford RJ, King AW, Deprez PH, De-Belleroche J, Freeman TC, Calam J: Effects of diet and the cholecystokinin antagonist; devazepide (L364,718) on CCK mRNA, and tissue and plasma CCK concentrations. Eur J Clin Invest 23:641-647,1993

34.    Pubols MH, Bartelt DC, Greene LJ: Trypsin inhibitor from human pancreas and pancreatic juice. J Biol Chem 249:2235-2242,1974

35.    Rehfeld JF: Cholecystokinin-from local gut hormone to ubiquitous messenger. Front Endocrinol (Lausanne) 8:47,2017

36.    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

37.    Spannagel AW, Green GM, Guan D, Liddle RA, Faull K, Reeve JR Jr: Purification and characterization of a luminal cholecystokinin-releasing factor from rat intestinal secretion. Proc Natl Acad Sci U S A 93:4415-4420,1996

38.    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

39.    Tsuzuki S, Fushiki T, Kondo A, Murayama H, Sugimoto E: Effect of a high-protein diet on the gene expression of a trypsin-sensitive, cholecystokinin-releasing peptide (monitor peptide) in the pancreas. Eur J Biochem 199:245-252,1991

40     Tsuzuki S, Miura Y, Fushiki T, Oomori T, Satoh T, Natori Y, Sugimoto E: Molecular cloning and characterization of genes encoding rat pancreatic cholecystokinin (CCK)-releasing peptide (monitor peptide) and pancreatic secretory trypsin inhibitor (PSTI). Biochim Biophys Acta 1132:199-202,1992

41.    Voet D, Voet JG: Biochemistry (2nd ed.). John Wiley & Sons (pp) 396-400,1995

42.    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

43.    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

44.    Yamanishi R, Kotera J, Fushiki T, Soneda T, Iwanaga T, Sugimoto E: Characteristic and localization of the monitor peptide receptor. Biosci Biotechnol Biochem 57:1153-1156,1993a

45.    Yamanishi R, Kotera J, Fushiki T, Soneda T, Saitoh T, Oomori T, Satoh T, Sugimoto E: A specific binding of the cholecystokinin-releasing peptide (monitor peptide) to isolated rat small-intestinal cells. Biochem J 291 ( Pt 1):57-63,1993b