Premium
A tyrosine kinase inhibitor‐induced myocardial degeneration in rats through off‐target phosphodiesterase inhibition
Author(s) -
Hu Wenyue,
Hirakawa Brad,
Jessen Bart,
Lee Michelle,
Aguirre Shirley
Publication year - 2012
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.2801
Subject(s) - milrinone , phosphodiesterase 3 , phosphodiesterase , endocrinology , cyclic adenosine monophosphate , hepatocyte growth factor receptor , medicine , calcium in biology , chemistry , intracellular , oxidative stress , calcium , pharmacology , biology , receptor , biochemistry , hepatocyte growth factor , enzyme , c met , inotrope
PF‐04254644 is a selective kinase inhibitor of mesenchymal epithelial transition factor/hepatocyte growth factor receptor with known off‐target inhibitory activity against the phosphodiesterase (PDE) family. Rats given repeated oral doses of PF‐04254644 developed a mild to moderate myocardial degeneration accompanied by sustained increase in heart rate and contractility. Investigative studies were conducted to delineate the mechanisms of toxicity. Microarray analysis of Sprague–Dawley rat hearts in a 6 day repeat dose study with PF‐04254644 or milrinone, a selective PDE3 inhibitor, revealed similar perturbation of the cyclic adenosine monophosphate (c‐AMP) pathway. PDE inhibition and activation of c‐AMP were further substantiated using PDE3B immunofluorescence staining and through a c‐AMP response element reporter gene assay. The intracellular calcium and oxidative stress signaling pathways were more perturbed by treatment with PF‐04254644 than milrinone. The rat cardiomyocytes calcium assay found a dose‐dependent increase in intracellular calcium with PF‐04254644 treatment. These data suggest that cardiotoxicity of PF‐04254644 was probably due to activation of c‐AMP signaling, and possibly subsequent disruption of intracellular calcium and oxidative stress signaling pathways. The greater response with PF‐04254644 as compared with milrinone in gene expression and micro‐ and ultrastructural changes is probably due to the broader panel of PDEs inhibition. Copyright © 2012 John Wiley & Sons, Ltd.