API

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Relationship: 2028

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Inhibition, trypsin leads to Increased monitor peptide

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Inhibition, trypsin
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Increased monitor peptide

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

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 Do not cite Under Development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

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) 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.  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

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. 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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. 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.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  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] .

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured 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].