ToxSci Advance Access originally published online on December 14, 2006
Toxicological Sciences 2007 96(1):184-193; doi:10.1093/toxsci/kfl190
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Evaluation of Two Novel Peptide Safety Markers for Exocrine Pancreatic Toxicity
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 W, Mail Zone T1A, Chesterfield, Missouri 63017. Fax: (314) 274-4426. E-mail: jennie.walgren{at}pfizer.com.
Received August 29, 2006; accepted November 29, 2006
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Abstract |
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Current markers of exocrine pancreatic toxicity have historically been poor indicators for both early diagnosis of disease and prediction of disease severity. Recently we identified two peptide markers (RA1609 and RT2864) of pancreatic toxicity that are target organ specific. In order to evaluate sensitivity of these markers versus current standard tests for pancreatic damage (i.e., lipase), we measured amylase and lipase, as well as RA1609 and RT2864 marker levels, in serum from rats treated with four doses (50–200 mg/kg) of the model pancreatic toxicant cyanohydroxybutene (CHB). In addition, to determine whether these peptide markers could detect pancreatic injury induced by different toxicants and in different species, we measured RA1609 and RT2864 marker levels in rats treated with the pancreatic toxicant caerulein, and in mice treated with CHB. RA1609 and RT2864 peptide markers proved to be more sensitive than amylase or lipase in detecting pancreatic damage, especially at an early time point (8 h) following CHB administration. The peptide markers also accurately predicted pancreatic injury induced by caerulein in rats. These markers were sensitive in detecting very mild pancreatic damage following CHB administration in mice, which are less susceptible to CHB-induced pancreatic toxicity. In addition, a species comparison of the RA1609 albumin fragment sequence indicated that cleavage of albumin from pancreatic proteases produces a similar fragment marker in several species, including humans. To determine whether the comparable human albumin fragment could be detected in sera from pancreatitis patients, we analyzed sera from normal individuals and from patients with diabetes, vasculitis, pancreatic cancer, and pancreatitis. It was found that markers corresponding to the fragments found in rat serum (RA1609 and RT2864) were present in human serum, and changes in these were indicative of and specific to pancreatitis. In conclusion, the RA1609 and RT2864 peptides are sensitive indicators of exocrine pancreatic damage that may be useful as safety markers for general pancreatic toxicity in multiple species.
Key Words: Pancreatitis; human; CHB; caerulein; SELDI; safety biomarkers.