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Key Event Title
Increased intestinal monitor peptide level
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Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|TI-induced AC tumors||KeyEvent||Arthur Author (send email)||Under development: Not open for comment. Do not cite||Under Development|
|All life stages||High|
Key Event Description
Trypsin-mediated feedback regulation of pancreatic exocrine secretion is commonly found among vertebrate species.
In rats, trypsin-sensitive monitor peptide (MP), a pancreatic soluble trypsin inhibitor (TI) found in pancreatic juice that protects against trypsin-induced auto-injury [Iwai K et al, 1987; Iwai K et al, 1988; Tsuzuki S et al, 1991; Tsuzuki S et al, 1992], plays a major role in stimulating pancreatic exocrine secretion via cholecystokinin (CCK) release [Miyasaka K et al, 1989; Fushiki T et al, 1989; Miyasaka K and Funakoshi A, 1998].
MP is a peptide consisting of 61 amino acids with a molecular weight of approximately 6000 and is secreted from pancreatic acinar cells along with other pancreatic enzymes [Iwai K et al, 1987].MP is reported to have trypsin inhibitory activity [Lin YZ et al, 1990], and it forms complexes with trypsin in the empty intestine, similar to other pancreatic soluble TIs [Voet D and Voet JG, 1995], which keeps the intestinal level of free MP low. However, once the gastric contents are transported to the small intestine, secretion of the pancreatic proteases with MP are induced, where trypsin is used for protein hydrolysis, and the level of free MP is subsequently increased [Iwai K et al, 1988; Graf R, 2006]. The increased MP level stimulates CCK release from I cells lining the small intestinal mucosa via MP receptors [Liddle RA et al, 1992; Yamanishi R et al, 1993; Yamanishi R et al, 1993; Liddle RA et al, 1992], and the resulting increase in CCK stimulates exocrine secretion from the pancreas. MP secretion is simultaneously increased to stimulate CCK release further. Therefore, MP-mediated regulation of trypsin and related proteases appears to act via a positive feedback loop as long as duodenal contents remain to consume trypsin for proteolysis.
In accordance with the increased secretion of pancreatic enzymes, proteolysis of the intestinal contents lowers protein levels in the intestinal lumen, which once again lowers the intestinal level of free MP due to the excess of trypsin. CCK release is decreased in accordance with the decreased intestinal MP level, followed by a decrease in pancreatic exocrine secretion [Liddle RA, 1995; Miyasaka K and Funakoshi A, 1998].
After ingestion of raw soya flour, which contains trypsin inhibitory activity, or TIs such as camostat, TI–trypsin complexes are formed, and the intestinal level of free MP is increased to stimulate CCK release [Yamanishi R et al, 1993], increasing the blood CCK level. Increased CCK further stimulates MP as well as other pancreatic enzymes via positive feedback regulation [Liddle RA, 1995].
How It Is Measured or Detected
No literatures that describe the methods of measuring intestinal concentration of MP are found although some authors reported the isolation and measurement of MP from synthesis reaction solution, pancreas or pancreatic juice.
Synthesized crude peptides were eluted through gel filtration chromatography. PSTI-I-specific peak was confirmed by mas spectrometric measurement and analytical HPLC was performed [Graf R et al, 2003].
In rats fed control and high protein diets, zymogen granules were isolated and concentrations of MP and PSTI-II in zymogen granules can be determined by HPLC [Tsuzuki S et al, 1991].
Rat anionic trypsinogen and a pancreatic secretory trypsin inhibitor were purified from the pure pancreatic juice of rats by reverse-phase HPLC [Iwai K et al, 1987].
Domain of Applicability
Feedback regulation of pancreatic enzyme secretion mediated by trypsin-sensitive intestinal peptides other than MP has been reported in mammals. Such peptides include luminal CCK-releasing factors (LCRFs) secreted by duodenal mucosal cells in response to intestinal diet in some mammalian species including rats, pigs (diazepam-binding inhibitor) and humans [Miyasaka K and Funakoshi A, 1998; Wang Y, 2002; Wang BJ and Cui ZJ, 2007]. In humans, different from rodents, LCRF is not secreted spontaneously in the intestine, however luminal amino acids and fatty acids were reported to induce CCK release [Liddle RA, 1997].
MP is one of pancreatic soluble TIs (PSTIs), which are found in the pancreatic juice of many mammalian species including pigs, dogs, 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: MP (or 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 CCK I cells via their surface MP receptors [Yamanishi R et al, 1993], whereas the latter does not [Guan D et al, 1990].
Human PSTIs do not directly stimulate CCK release from intestinal mucosal cells [Miyasaka K et al, 1989], and no PSTI except MP has been reported to stimulate CCK release.
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