title: Evaluation of miR-216a and miR-217 as Potential Biomarkers of Acute Exocrine Pancreatic Toxicity in Rats.
abstract: Detecting and monitoring exocrine pancreatic damage during nonclinical and clinical testing is challenging because classical biomarkers amylase and lipase have limited sensitivity and specificity. Novel biomarkers for drug-induced pancreatic injury are needed to improve safety assessment and reduce late-stage attrition rates. In a series of studies, miR-216a and miR-217 were evaluated as potential biomarkers of acute exocrine pancreatic toxicity in rats. Our results revealed that miR-216a and miR-217 were almost exclusively expressed in rat pancreas and that circulating miR-216a and miR-217 were significantly increased in rats following administration of established exocrine pancreatic toxicants caerulein (CL) and 1-cyano-2-hydroxy-3-butene (CHB) as well as in rats administered a proprietary molecule known to primarily affect the exocrine pancreas. Conversely, neither microRNA was increased in rats administered a proprietary molecule known to cause a lesion at the pancreatic endocrine-exocrine interface (EEI) or in rats administered an established renal toxicant. Compared with amylase and lipase, increases in miR-216a and miR-217 were of greater magnitude, persisted longer, and/or correlated better with microscopic findings within the exocrine pancreas. Our findings demonstrate that in rats, miR-216a and miR-217 are sensitive and specific biomarkers of acute exocrine pancreatic toxicity that may add value to the measurement of classical pancreatic biomarkers.
authors.affiliation: 1 Drug Safety R&D, Pfizer Inc., San Diego, California, USA.
authors.forename: Jianying
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1 Drug Safety R&D, Pfizer Inc., San Diego, California, USA.
authors.forename: Wenhu
authors.initials: W
authors.lastname: Huang
authors.affiliation: 1 Drug Safety R&D, Pfizer Inc., San Diego, California, USA.
authors.forename: Stephane
authors.initials: S
authors.lastname: Thibault
authors.affiliation: 2 Drug Safety R&D, Pfizer Inc., Groton, Connecticut, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Brown
authors.affiliation: 2 Drug Safety R&D, Pfizer Inc., Groton, Connecticut, USA.
authors.forename: Walter
authors.initials: W
authors.lastname: Bobrowski
authors.affiliation: 3 Pharm Sci Pharmaceutical R&D, Pfizer Inc., San Diego, California, USA.
authors.forename: Hovhannes J
authors.initials: HJ
authors.lastname: Gukasyan
authors.affiliation: 1 Drug Safety R&D, Pfizer Inc., San Diego, California, USA.
authors.forename: Winston
authors.initials: W
authors.lastname: Evering
authors.affiliation: 1 Drug Safety R&D, Pfizer Inc., San Diego, California, USA.
authors.forename: Wenyue
authors.initials: W
authors.lastname: Hu
authors.affiliation: 1 Drug Safety R&D, Pfizer Inc., San Diego, California, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: John-Baptiste
authors.affiliation: 1 Drug Safety R&D, Pfizer Inc., San Diego, California, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Vitsky
mesh_terms: D000208:Acute Disease; D000475:Alkenes / Q000633:toxicity; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002108:Ceruletide / Q000633:toxicity; D010188:Exocrine Pancreatic Insufficiency / Q000097:blood* / Q000378:metabolism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000097:blood* / Q000378:metabolism; D009570:Nitriles / Q000633:toxicity; D009928:Organ Specificity; D046790:Pancreas, Exocrine / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012680:Sensitivity and Specificity
chemical_list: D000475:Alkenes; D015415:Biomarkers; C578536:MIRN216 microRNA, rat; C000623105:MIRN217 microRNA, rat; D035683:MicroRNAs; D009570:Nitriles; C055903:1-cyano-2-hydroxy-3-butene; D002108:Ceruletide
keywords: biomarkers; caerulein; cyanohydroxybutene; exocrine pancreas; microRNA; pancreatic toxicity