Acute lymphoid and gastrointestinal toxicity induced by selective p38alpha map kinase and map kinase-activated protein kinase-2 (MK2) inhibitors in the dog.
Exposure to moderately selective p38alpha mitogen-activated protein kinase (MAPK) inhibitors in the Beagle dog results in an acute toxicity consisting of mild clinical signs (decreased activity, diarrhea, and fever), lymphoid necrosis and depletion in the gut-associated lymphoid tissue (GALT), mesenteric lymph nodes and spleen, and linear colonic and cecal mucosal hemorrhages. Lymphocyte apoptosis and necrosis in the GALT is the earliest and most prominent histopathologic change observed, followed temporally by neutrophilic infiltration and acute inflammation of the lymph nodes and spleen and multifocal mucosal epithelial necrosis and linear hemorrhages in the colon and cecum. These effects are not observed in the mouse, rat, or cynomolgus monkey. To further characterize the acute toxicity in the dog, a series of in vivo, in vitro, and immunohistochemical studies were conducted to determine the relationship between the lymphoid and gastrointestinal (GI) toxicity and p38 MAPK inhibition. Results of these studies demonstrate a direct correlation between p38alpha MAPK inhibition and the acute lymphoid and gastrointestinal toxicity in the dog. Similar effects were observed following exposure to inhibitors of MAPK-activated protein kinase-2 (MK2), further implicating the role of p38alpha MAPK signaling pathway inhibition in these effects. Based on these findings, the authors conclude that p38alpha MAPK inhibition results in acute lymphoid and GI toxicity in the dog and is unique among the species evaluated in these studies.
Morris
Dale L
DL
Pfizer Inc., Drug Safety R&D, Research, Pharmacokinetics, Dynamics & Metabolism, and Pharmaceutical Sciences, St. Louis, Missouri, USA. dale.1.morris@pfizer.com
O'Neil
Shawn P
SP
Devraj
Rajesh V
RV
Portanova
Joseph P
JP
Gilles
Richard W
RW
Gross
Cindy J
CJ
Curtiss
Sandra W
SW
Komocsar
Wendy J
WJ
Garner
Debra S
DS
Happa
Fernando A
FA
Kraus
Lori J
LJ
Nikula
Kristen J
KJ
Monahan
Joseph B
JB
Selness
Shaun R
SR
Galluppi
Gerald R
GR
Shevlin
Kimberly M
KM
Kramer
Jeffrey A
JA
Walker
John K
JK
Messing
Dean M
DM
Anderson
David R
DR
Mourey
Robert J
RJ
Whiteley
Laurence O
LO
Daniels
John S
JS
Yang
Jerry Z
JZ
Rowlands
Philip C
PC
Alden
Carl L
CL
Davis
John W
JW
Sagartz
John E
JE
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003106:Colon / Q000187:drug effects / Q000473:pathology; D004285:Dogs; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000473:pathology; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016014:Linear Models; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008206:Lymphatic Diseases / Q000139:chemically induced* / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D023382:Toxicity Tests, Acute; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2