Skip Navigation


ToxSci Advance Access originally published online on December 14, 2006
Toxicological Sciences 2007 96(1):174-183; doi:10.1093/toxsci/kfl189
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
96/1/174    most recent
kfl189v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Walgren, J. L.
Right arrow Articles by Thompson, D. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Walgren, J. L.
Right arrow Articles by Thompson, D. C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Identification of Novel Peptide Safety Markers for Exocrine Pancreatic Toxicity Induced by Cyanohydroxybutene

Jennie L. Walgren1, Michael D. Mitchell, Laurence O. Whiteley and David C. Thompson

Pfizer Global Research and Development, Drug Safety Research and Development, Chesterfield, Missouri 63017

1 To whom correspondence should be addressed at Pfizer Global Research and Development, Drug Safety Research and Development, 700 Chesterfield Parkway West, Mail Zone T1A, Chesterfield, MO 63017. Fax: (314) 274-4426. E-mail: jennie.walgren{at}pfizer.com.

Received August 29, 2006; accepted November 29, 2006


  Abstract

Historically, serum amylase and lipase levels have been used to indicate pancreas injury; however, these enzyme levels are often not predictive of pathology. In an effort to discover novel biomarkers of pancreatic acinar cell injury, we analyzed serum and pancreas tissue from cyanohydroxybutene (CHB)–treated male IGS rats using proteomics methods. CHB produces an "edematous pancreatitis," characterized by depletion of zymogen granules, acinar cell apoptosis, and mild to moderate inflammation. Secondary necrosis occurs at higher doses. Rats were treated with 150 mg/kg of CHB and samples were collected at 4, 8, and 24 h. Analyses of serum tryptic digests by surface-enhanced laser desorption-ionization mass spectrometry revealed two novel peptide biomarkers (RA1609 and RT2864) that were predictive of pancreatic damage. Levels of RA1609 decreased, while levels of RT2864 increased by 8 h following CHB treatment. The changes in RA1609 and RT2864 were detected in media from CHB-treated primary rat acini, demonstrating that these peptides are either of pancreatic cell origin or are produced by proteases released from acinar cells. Sequencing revealed that RA1609 is a fragment of rat albumin (accession number P02770 [GenBank] , residues 348–360) and RT2864 is a portion of either rat trypsin III (accession number P08426 [GenBank] , residues 39–65) or bovine trypsin (accession number P00760 [GenBank] , residues 35–61). These two peptides, and possibly other fragments of serum proteins that are digested by pancreatic proteases, may be useful as safety markers for exocrine pancreatic toxicity during drug development or as biomarkers for the diagnosis and/or grading of severity of pancreatic disease.

Key Words: pancreatitis; CHB; SELDI; safety biomarkers.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
V. P. Singh, G. D. Bren, A. Algeciras-Schimnich, D. Schnepple, S. Navina, S. A. Rizza, R. K. Dawra, A. K. Saluja, S. T. Chari, S. S. Vege, et al.
Nelfinavir/ritonavir reduces acinar injury but not inflammation during mouse caerulein pancreatitis
Am J Physiol Gastrointest Liver Physiol, May 1, 2009; 296(5): G1040 - G1046.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.