title: Hyalinization of the pyloric stomach in CD-1 mice following oral (dietary) administration of the corticosteroid agonists mometasone furoate, budesonide, and flunisolide.
abstract: The purpose of this study was to compare the toxicity of three marketed corticosteroid receptor agonists (mometasone furoate, budesonide, or flunisolide) to the stomach of female CD-1 mice following oral administration via the diet for up to 52 weeks, with a 16-week recovery period (budesonide and flunisolide). A range of tissues was examined by light microscopy, accompanied by clinical pathology measurements to assess anticipated corticosteroid effects as a surrogate marker of systemic drug exposure. Microscopic changes seen in the stomach with each corticosteroid included pyloric hyalinization. This previously unreported finding was investigated using histochemical and immunohistochemical techniques and was found to consist of hyalinized collagen, in association with increased immunohistochemical signal for transglutaminase-2 and osteopontin. The significance of the osteopontin finding is unclear; however, the ability of transglutaminase-2 to facilitate the formation of degradation resistant protein bonds implies this protein may be involved in the pathogenesis of this change. Furthermore, published evidence that transglutaminase-2 may be induced by a corticosteroid agonist raises the possibility that pyloric stomach hyalinization may be a class effect of corticosteroids via the action of this enzyme.
authors: Safety Assessment, GlaxoSmithKline, Ware, UK. tom.p.mckevitt@gsk.com
authors: Tom P
authors: TP
authors: McKevitt
authors: Paul
authors: P
authors: Giffen
authors: Jennie A
authors: JA
authors: Woodfine
authors: Sean J
authors: SJ
authors: McCawley
authors: Steve A
authors: SA
authors: Papworth
authors: Paul
authors: P
authors: McGill
authors: Jan
authors: J
authors: Osborne
authors: Paul
authors: P
authors: Beard
authors: Tom C
authors: TC
authors: Williams
authors: Jan
authors: J
authors: Klapwijk
authors: David J
authors: DJ
authors: Lewis
mesh_terms: D000284:Administration, Oral; D000305:Adrenal Cortex Hormones / Q000819:agonists* / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000633:toxicity*; D019819:Budesonide / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005446:Fluocinolone Acetonide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D019204:GTP-Binding Proteins / Q000378:metabolism; D006818:Hyalin / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008854:Microscopy, Electron; D000068656:Mometasone Furoate; D053495:Osteopontin / Q000378:metabolism; D011244:Pregnadienediols / Q000008:administration & dosage / Q000633:toxicity*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011708:Pylorus / Q000033:anatomy & histology / Q000378:metabolism*; D011503:Transglutaminases / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D011244:Pregnadienediols; D000068656:Mometasone Furoate; D005446:Fluocinolone Acetonide; D053495:Osteopontin; D019819:Budesonide; C007734:flunisolide; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins