To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:2031

Relationship: 2031

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 acinar cell exocrine secretion leads to Acinar cell proliferation

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 Shigeru Hisada (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 Do not cite Under Development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 Moderate NCBI
Macaca fascicularis Macaca fascicularis Moderate 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

In rats, an increased blood level of CCK stimulates pancreatic acinar cells to secrete digestive enzymes directly via surface CCK1 receptors and indirectly via innervation of vagal afferent nerves expressing CCK1 receptors. A persistent increase in the blood CCK level stimulates pancreatic acinar cell proliferation directly via surface CCK1 receptors. On the other hand, human pancreatic acinar cells express CCK2 receptors, which do not respond to CCK in terms of secretion and proliferation. Pancreatic enzyme secretion in humans is innervated by afferent vagal nerves expressing CCK1 receptors; however, its involvement in acinar cell proliferation is unclear.

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

CCK-induced pancreatic acinar cell proliferation

An increased plasma level of CCK directly induces proliferation of pancreatic acinar cells via surface CCK1 receptors as well as exocrine secretion in rodents. Consuming raw soya flour for 30 days, administration of trypsin inhibitor in drinking water for 7 days, or repeated injection of cholecystokinin for 7 days induced pancreatic hypertrophy and hyperplasia [Yanatori Y and Fujita T, 1976]. Repeated administration of CCK for 21 days [Folsch UR et al, 1978] and treatment with the CCK8 and CCK1 receptor agonist A-71623 for 3 weeks [Povoski SP et al, 1994] also induced pancreatic hyperplastic changes in mice [Tashiro M et al, 2004]. Addition of 0.1% camostat in the diet for 10 days increased pancreatic weight and protein and DNA levels in a time-dependent manner in mice [Tashiro M et al, 2004].

The CCK1 receptor agonist GI181771X induced pancreatitis due to abnormal basolateral secretion of Zymogen granules at the high dose and acinar cell hypertrophy at the middle and low doses in ratsan. The author mentioned JAK1/2–STAT1/3 activation leading to p38MAPK activation as a mechanism underlying acinar cell proliferation.

Direct effect of CCK on acinar cell proliferation via CCK receptors

In rats, the trypsin inhibitor FOY-305 increased pancreatic weight and induced acinar cell hypertrophy, and denervation of vagal nerves had little effect on these hypertrophic changes [Aki T et al, 1989]. Administration of CCK-8 at physiological doses induced exocrine secretion, and atropine and vagal nerve denervation suppressed this exocrine secretion but not that induced by non-physiological doses of CCK-8 [Li Y and Owyang C, 1993]. These results suggest that the involvement of vagal nerve innervation in acinar cell proliferation under an increased blood CCK level might be low, and this may also be the case in humans, but the evidence is unclear [Chandra R and Liddle RA, 2009].

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

A8947, a broadleaf herbicide with trypsin inhibitory action, was fed to male rats for up to 28 days, at doses of 0, 300, 10,000, and 30,000 ppm. A8947 at 10,000 and 30,000 ppm induced significant increases in acinar cell proliferation after 7 days, followed by a decrease to control levels by 28 days [Obourn JD et al, 1997]. The reason why the TI-induced increase in acinar cell proliferation is transient is unclear.

In humans, the involvement of innervation of vagal nerves in acinar cell proliferation under an increased blood level of CCK might be low, but this is unclear [Chandra R and Liddle RA, 2009].

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

KE3 and KE4 in rats injected with CCK

In rats repeatedly injected subcutaneously with CCK at 7.5 or 30 Ivy dog units (IU) twice daily for 20 days, pancreatic wet weight and DNA content / 100g BW increased with a same manner compared with saline-treated rats, however, pancreatic output of amylase and trypsin in response to submaximal intravenous stimulation with CCK at 15 IU/kg/hour increased with dose-dependent manner. [Folsch UR et al, 1978].

KE3 and KE4 in rats treated with TIs

A8947, a broadleaf herbicide with trypsin inhibitory action, was fed to male rats for up to 28 days, at doses of 0, 300, 10,000, and 30,000 ppm, or 56 days, at 0 and 30,000 ppm. A8947 at 10,000 and 30,000 ppm induced significant increases in pancreatic weight, acinar cell proliferation, diffuse acinar cell hypertrophy, and the plasma CCK level after 7 days. The increases in pancreatic weight and the CCK level were maximum at day 14 and then maintained throughout the study, whereas acinar cell proliferation peaked at day 7 but then decreased to control levels by day 28 [Obourn JD et al, 1997]. MK-329, a specific CCKA receptor antagonist, completely abolished the increase in pancreatic weight induced by 30,000 ppm A8947 after 7 days [Obourn JD et al, 1997].

Weanling male Wistar rats were fed 15 diets consisting of four concentrations of purified soybean TIs (93, 215, 337, and 577 mg/100 g diet) and three protein concentrations (10%, 20%, and 30%), as well as raw and heat-treated soy flour containing 10% protein. Rats were sacrificed at 3-month intervals, starting at 6 months, over a period of 22 months [Rackis JJ et al, 1985]. Trypsin and chymotrypsin activities per 100g BW, RNA and DNA contents of pancreas indicative of pancreatic hypertrophy and hyperplasia, respectively, were already increased in all of the TI and protein-fed animals after 6-month dosing, although pancreatic nodules were increased in number at 15 months of dosing or later at 215 mg TI/100 g diet or higher [Liener IE et al, 1985].

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

In rats in which bile and pancreatic juice had been returned to the duodenum, intraduodenal administration of 30 mg RSF stimulated a 1-h integrated increase in pancreatic protein output of 2.2 ± 1.1 mg/h (mean ± SE) [Jordinson M et al, 1996].

Pancreatic hypertrophy was observed in rats fed an RSF-containing diet within 9 days [Rackis JJ, 1965; Watanapa P and Williamson RC, 1993].

Rats fed RSF showed a biphasic increase in acinar and duct cell proliferation, as determined by [3H]-thymidine incorporation into pancreatic DNA, on days 2–4 and again on days 7–28 after the start of RSF feeding. The first peak in DNA synthesis may represent a regenerative response to tissue damage. The second more delayed peak appears to represent the development of hyperplasia in response to a trophic stimulus [Oates PS and Morgan RG, 1984].

Rats administered TIs in drinking water for 7 days or repeatedly injected with CCK for 7 days [Yanatori Y and Fujita T, 1976] exhibited mitotic figures in the acinar, centroacinar, and intercalated portions of the pancreas and in excretory duct cells, as well as marked pancreatic hypertrophy [Oates PS and Morgan RG, 1984].

A8947, a broadleaf herbicide with trypsin inhibitory action, was fed to male rats for up to 28 days, at doses of 0, 300, 10,000, and 30,000 ppm. A8947 at 10,000 and 30,000 ppm induced significant increases in acinar cell proliferation after 7 days, followed by a decrease to control levels by 28 days [Obourn JD et al, 1997].

In the abovementioned studies [Rackis JJ et al, 1985; Liener IE et al, 1985], the increases in exocrine activity and acinar cell hyperplasia and hypertrophy were found at the earliest sacrifice (6 months). The exocrine activities and hypertrophic changes remained unchanged thereafter, whereas the hyperplastic changes became more pronounced until the final sacrifice (22 months).

These findings show that pancreatic exocrine secretion and increased acinar cell proliferation were found at 1 h and 7 days, respectively, after the start of TI or CCK treatment.

CCK was released within 1 h after intraduodenal administration of RSF, and acinar cell proliferation was elevated approximately 7 days after the start of RSF feeding, although some TIs induced transient acinar cell proliferation within 7 days as a regenerative change to acute pancreatic injury.

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

TIs including RSFs are reported to induce pancreatic acinar cell proliferation as well as acinar cell hypertrophy due to increased pancreatic protein secretion in rats. Administration of CCK receptor agonist and CCK also induce acinar cell hyperplasia and hypertrophy as follows.

Acinar cell changes induced by a CCK receptor agonist

A novel CCK1 receptor agonist, GI181771X, was administered to mice and/or rats at doses of 0.25–250 mg/kg/day from 7 days to 26 weeks, and pancreatic acinar cell responses were examined. The treated animals showed a wide range of morphological changes in the pancreas that were dose and time dependent, including necrotizing pancreatitis, acinar cell hypertrophy/atrophy, zymogen degranulation, focal acinar cell hyperplasia, and interstitial inflammation [Myer JR et al, 2014].

Acinar cell proliferation in rats injected with CCK

Rats 1) fed raw soybeans for 30 days, 2) administered TIs in drinking water for 7 days, or 3) repeatedly injected with CCK for 7 days exhibited increased mitotic figures in the acinar, centroacinar, and intercalated portions of the pancreas and in excretory duct cells, as well as marked pancreatic hypertrophy [Myer JR et al, 2014].

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

TBD

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

The effect of CCK on acinar cell proliferation differs between rodents and humans.

In rats, CCK stimulates pancreatic exocrine secretion directly via CCK1 receptors expressed on the cell surface and also via innervation of afferent vagal nerves expressing CCK1 receptors [Singer MV and Niebergall-Roth E, 2009; Pandiri AR, 2014]. Higher plasma levels of CCK might also directly stimulate acinar cell proliferation via surface CCK receptors [Yamamoto M et al, 2003].        

In contrast to rats, monkeys receiving repeated doses of the CCK1 receptor agonist GI181771X for up to 52 weeks showed no hypertrophy or histopathological changes in the pancreas [Myer JR et al, 2014]. Regarding 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]. Moreover, some epidemiological surveys suggested that long-term ingestion of TI-containing foods does not increase the risk of pancreatic cancer [Miller RV, 1978], although oral ingestion of raw soya flour containing TIs was reported to stimulate CCK release in humans [Calam J et al, 1987].

These findings suggest that exocrine secretion in humans and primates is regulated exclusively by innervation of vagal afferent nerves expressing CCK1 receptors [Soudah HC et al, 1992; Beglinger C et al, 1992; Singer MV and Niebergall-Roth E, 2009], with little effect on acinar cell proliferation, although the possibility of direct stimulation of exocrine secretion from human pancreatic acinar cells has been suggested [Murphy JA et al, 2008].

Meanwhile, a strong relationship between pancreatic cancers and a history of subtotal gastrectomy [Mack TM et al, 1986], which induced a higher plasma CCK level in response to fat [Hopman WP et al, 1984], was reported. Therefore, the effect of CCK on acinar cell proliferation in humans is controversial.

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.      Aki T, Baba N, Tobe T, Suzuki T, Nishimura I, Tsai G: [The influence of truncal vagotomy or surgical sympathectomy on the pancreatic trophic effect of trypsin inhibitor upon normal rats and major pancreatectomized rats]. Nihon Geka Gakkai Zasshi 90:586-597,1989

 2.    Beglinger C, Hildebrand P, Adler G, Werth B, Luo H, Delco F, Gyr K: Postprandial control of gallbladder contraction and exocrine pancreatic secretion in man. Eur J Clin Invest 22:827-834,1992

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

 4.    Chandra R, Liddle RA: Neural and hormonal regulation of pancreatic secretion. Curr Opin Gastroenterol 25:441-446,2009

 5.    Crass RA, Morgan RG: The effect of long-term feeding of soya-bean flour diets on pancreatic growth in the rat. Br J Nutr 47:119-129,1982

 6.    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

 7.    Hopman WP, Jansen JB, Lamers CB: Plasma cholecystokinin response to oral fat in patients with Billroth I and Billroth II gastrectomy Ann Surg 199:276-280,1984

 8.    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

 9.    Jordinson M, Deprez PH, Playford RJ, Heal S, Freeman TC, Alison M, Calam J: Soybean lectin stimulates pancreatic exocrine secretion via CCK-A receptors in rats. Am J Physiol 270:G653-9,1996

10.    Li Y, Owyang C: Vagal afferent pathway mediates physiological action of cholecystokinin on pancreatic enzyme secretion. J Clin Invest 92:418-424,1993

11.    Liener IE, Nitsan Z, Srisangnam C, Rackis JJ, Gumbmann MR: The USDA trypsin inhibitor study. II. Timed related biochemical changes in the pancreas of rats. Qual Plant Foods Hum Nutr 35:243-257,1985

12.    Mack TM, Yu MC, Hanisch R, Henderson BE: Pancreas cancer and smoking, beverage consumption, and past medical history. J Natl Cancer Inst 76:49-60,1986

13.    Miller RV: Epidemiology. Alan R. Liss, New York (pp) 39-57,1978

14.    Murphy JA, Criddle DN, Sherwood M, Chvanov M, Mukherjee R, McLaughlin E, Booth D, Gerasimenko JV, Raraty MG, Ghaneh P, Neoptolemos JP, Gerasimenko OV, Tepikin AV, Green GM, Reeve JR Jr, Petersen OH, Sutton R: Direct activation of cytosolic Ca2+ signaling and enzyme secretion by cholecystokinin in human pancreatic acinar cells. Gastroenterology 135:632-641,2008

15.    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

16.    Oates PS, Morgan RG: Short-term effects of feeding raw soya flour on pancreatic cell turnover in the rat. Am J Physiol 247:G667-73,1984

17.    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

18.    Pandiri AR: Overview of exocrine pancreatic pathobiology. Toxicol Pathol 42:207-216,2014

19.    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

20.    Rackis JJ: Physiological properties of soybean trypsin inhibitors and their relationship to pancreatic hypertrophy and growth inhibition of rats.. Fed Proc 24:1488-1493,1965

21.    Rackis JJ, Gumbmann MR, Liener IE: The USDA trypsin inhibitor study. I. Background, objectives, and procedural details. Qual Plant Foods Hum Nutr 35:213-24,1985

22.    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

23.    Soudah HC, Lu Y, Hasler WL, Owyang C: Cholecystokinin at physiological levels evokes pancreatic enzyme secretion via a cholinergic pathway. Am J Physiol 263:G102-107,1992

24.    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

25.    Watanapa P, Williamson RC: Experimental pancreatic hyperplasia and neoplasia: effects of dietary and surgical manipulation. Br J Cancer 67:877-884,1993

26.    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

27.    Yanatori Y, Fujita T: Hypertrophy and hyperplasia in the endocrine and exocrine pancreas of rats fed soybean trypsin inhibitor or repeatedly injected with pancreozymin. Arch Histol Jpn 39:67-78,1976