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Relationship: 2028

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

Inhibition, trypsin leads to Increased monitor peptide

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 Moderate Low 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 Do not cite Under Development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 acinar cells secrete digestive enzymes including trypsin into the small intestine.

In rats, one of the pancreatic soluble trypsin inhibitors (TIs), monitor peptide (MP), is simultaneously secreted in the pancreatic juice. MP forms complexes with trypsin in the empty intestine, which keeps the intestinal level of free MP low. Once the gastric contents are transported to the small intestine, secretion of the pancreatic proteases including trypsin and MP is induced, where trypsin is used for protein hydrolysis, and the level of free MP is subsequently increased. The increased MP level stimulates CCK release from I cells lining the small intestinal mucosa via MP receptors, and the resulting increase in CCK stimulates exocrine secretion including MP from the pancreas. Increased MP further stimulates CCK secretion via a positive feedback loop as long as duodenal contents remain to consume trypsin for proteolysis.

After trypsin inhibitors are ingested, the intestinal content of free MP increases rapidly, especially in an empty intestine, via positive feedback regulation.

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

Trypsin is a digestive enzyme secreted by pancreatic acinar cells that cleaves peptide bonds at the carboxyl end of basic amino acids (lysine and arginine). Secretion of pancreatic digestive enzymes including trypsin is regulated mainly by cholecystokinin (CCK) released from enteroendocrine I cells located in the duodenal mucosa of the small intestine [Wang BJ and Cui ZJ, 2007], and CCK release is controlled by multiple mechanisms [Caron J et al, 2017]. These mechanisms involve feedback regulation of trypsin-sensitive CCK-releasing peptides, one being positive feedback regulation of MP and the other negative feedback regulation of luminal CCK-releasing factor (LCRF) [Miyasaka K and Funakoshi A, 1998; Wang BJ and Cui ZJ, 2007; Guan D et al, 1990].

MP is one of the PSTIs in rats, which stimulates CCK release from duodenal enteroendocrine I cells as well as inhibition of trypsin activity. MP consists of 61 amino acids and has a molecular weight of approximately 6000. MP was first purified from rat pancreatic juice, and its amino acid sequence was subsequently determined [Iwai K et al, 1987; Lin YZ et al, 1990].

MP is bound to trypsin in the empty intestine. Once gastric contents are transported into the small intestine, secretion of the pancreatic proteases with MP is increased, where trypsin instead hydrolyzes these proteins, leading to an increase in the free MP level [Iwai K et al, 1988; Liddle RA, 1995; Graf R, 2006]. The increased level of MP stimulates CCK release from I cells, and then pancreatic exocrine secretion is stimulated [Liddle RA et al, 1992; Guan D et al, 1990; Cuber JC et al, 1990]. It was shown that MP binds to the surface of CCK-immunoreactive mucosal cells of the small intestine [Yamanishi R et al, 1993a; Yamanishi R et al, 1993b].

Following the increased secretion of pancreatic enzymes, proteolysis decreases intestinal protein contents, which once again decreases the intestinal level of free MP due to the excess of trypsin and in turn CCK release [Liddle RA, 1995; Miyasaka K and Funakoshi A, 1998; Graf R, 2006].

When raw soya flour (RSF), which contains trypsin inhibitory activity, or TIs such as camostat are ingested, trypsin activity is inhibited to increase the intestinal level of free MP especially in the empty intestine, followed by an increase in the blood level of CCK [Liddle RA, 1995; Miyasaka K and Funakoshi A, 1998]. TI ingestion-induced increases in blood levels of CCK leads to further CCK release due to increased pancreatic secretion of proteins including MP in a positive feedback manner. On the other hand, TIs may elevate the luminal concentration of LCRF to stimulate CCK release; however, this increase might not be as exaggerated as that of MP, because increased blood level of CCK does not induce further secretion of LCRF.

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

In normal rats, positive regulation of CCK release by MP seems to require some level of pancreatic secretion before to be effective. In the presence of nutritional protein in the duodenum, trypsin is used for digestion of protein and increased levels of MP stimulates CCK release. On the other hand, after most of the protein is digested, increased free MP might be inactivated with excess of trypsin or other proteases, as follows [Foltz M, 2008]:

1) MP is degraded by trypsin and other proteases.

2) MP forms a complex with trypsin as other PSTIs.

3) MP forms a complex with trypsin, thereafter degraded by proteases.

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

No study has shown a direct quantitative relationship between MIE and KE1.

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

No study has reported the time from trypsin inhibition to alteration of intestinal MP content. However, as mentioned above, treatment with trypsin inhibitors or MP increased the plasma concentration of CCK within 30 min in rats.

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

Raw soya flour and trypsin inhibitors such as camostat inhibit trypsin activity, leading to an increase in CCK release from the upper intestine into the bloodstream, where the increased CCK released seems to be mediated by increased luminal concentration of MP due to trypsin inhibition [Green GM and Miyasaka K, 1983; Liddle RA et al, 1984; Goke B et al, 1986; 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; Calam J et al, 1987] .

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

MP stimulates CCK release from intestinal I cells, and the increased CCK level in turn promotes pancreatic acinar cells to secrete pancreatic enzymes including CCK-stimulating MP. Therefore, MP-mediated CCK release is under positive feedback regulation [Liddle RA, 1995; Wang BJ and Cui ZJ, 2007; Chey WY and Chang T, 2001], and the effects of trypsin inhibitors seem robust. As discussed previously, trypsin-sensitive LCRF released from intestinal mucosal cells also stimulate duodenal I cells to release CCK with negative feedback loop.

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

Isoforms of trypsin are found in many species, for example, cationic and anionic trypsins (trypsins 1 and 2) and mesotrypsin in humans, cationic and anionic trypsins in cows, and anionic trypsin and P23 in rats [Chen JM and Claude Férec C, 2013; Fukuoka S and Nyaruhucha CM, 2002] . Despite differences among species, the three-dimensional structures of the isoforms are highly conserved among species, and the natural substrates for the enzymes are generally any peptide that contains Lys or Arg [Baird Jr TT, 2017]. The active site of trypsin has a specific catalytic triad structure composed of serine, histidine, and aspartate, and the flanking amino acid sequences are entirely conserved [Baird Jr TT and Craik CS, 2013; Baird Jr TT, 2017]. Therefore, trypsin inhibitors have comparable effects on the enzymatic activity of trypsin isoforms among animal species including humans and rats [Savage GP and Morrison SC, 2003].

MP secreted from rat pancreatic acinar cells into the small intestine stimulates I cells of the small intestinal mucosa to release CCK.

MP-like peptides are also found in rats and other mammalian species [Eddeland A and Ohlsson K, 1976]. Rat soluble trypsin inhibitor [Tsuzuki S et al, 1992; Tsuzuki S et al, 1991], human soluble trypsin inhibitor [Pubols MH et al, 1974; Kikuchi N et al, 1985], and bovine soluble trypsin inhibitor [Greene LJ and Giordano JS Jr, 1969; Guy O et al, 1971] are homologous peptides, all of which show trypsin inhibitory activity but no CCK-stimulatory activity [Miyasaka K et al, 1989a; Miyasaka K et al, 1989b; Marchbank T et al, 1998; Voet D and Voet JG, 1995].

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.    Baird Jr TT, Craik CS: Trypsin. Academic Press, Cambridge, Massachusetts (pp)2594-2600,2013

 2.    Baird Jr TT: Trypsin. Elsevier,2017

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

 4.    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

 5.    Chen J-M, Claude Férec C: Human trypsins. Academic Press, Cambridge, Massachusetts (pp) 2600-2609,2013

 6.    Chey WY, Chang T: Neural hormonal regulation of exocrine pancreatic secretion. Pancreatology 1:320-335,2001

 7.    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

 8.    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

 9.    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

10.    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

11.    Fukuoka S, Nyaruhucha CM: Expression and functional analysis of rat P23, a gut hormone-inducible isoform of trypsin, reveals its resistance to proteinaceous trypsin inhibitors. Biochim Biophys Acta 1588:106-112,2002

12.    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

13.    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

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

15.    Green GM, Miyasaka K: Rat pancreatic response to intestinal infusion of intact and hydrolyzed protein. Am J Physiol 245:G394-8,1983

16.    Greene LJ, Giordano JS Jr: The structure of the bovine pancreatic secretory trypsin inhibitor--Kazal's inhibitor. I. The isolation and amino acid sequences of the tryptic peptides from reduced aminoethylated inhibitor. J Biol Chem 244:285-298,1969

17.    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

18.    Guy O, Shapanka R, Greene LJ: The structure of the bovine pancreatic secretory trypsin inhibitor--Kazal's inhibitor. 3. Determination of the disulfide bonds and proteolysis by thermolysin. J Biol Chem 246:7740-7747,1971

19.    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

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

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

22.    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

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

24.    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

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

26.    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

27.    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

28.    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

29.    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

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

31.    Obourn JD, Frame SR, Chiu T, Solomn TE, Cook JC: Evidence that A8947 enhances pancreas growth via a trypsin inhibitor mechanism.Toxicol Appl Pharmacol 146:116-126,1997

32.    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

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

34.    Savage GP, Morrison SC: Trypsin inhibitors. Elsevier (pp) 5878-5884,2003

35.    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

36.    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

37.    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

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

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

40.    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

41.    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