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.

Links

Publisher Full Text

Authors

McKevitt TP, Giffen P, Woodfine JA, McCawley SJ, Papworth SA, McGill P, Osborne J, Beard P, Williams TC, Klapwijk J, Lewis DJ

Institution

Safety Assessment, GlaxoSmithKline, Ware, UK. tom.p.mckevitt@gsk.com

Source

Toxicologic pathology 39:6 2011 Oct pg 958-68

MeSH

Administration, Oral
Adrenal Cortex Hormones
Animals
Anti-Inflammatory Agents
Budesonide
Female
Fluocinolone Acetonide
GTP-Binding Proteins
Hyalin
Mice
Mice, Inbred Strains
Microscopy, Electron
Osteopontin
Pregnadienediols
Pylorus
Transglutaminases

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21885873