Dexamethasone megadoses stabilize rat liver lysosomal membranes by non-genomic and genomic effects

Purpose. Membrane-stabilizing effects map be part of glucocorticoid action during high-dose glucocorticoid therapy. The present study investigates the mode of action of dexamethasone megadoses on rat liver lysosomal membranes. Methods. Following intravenous administration of dexamethasone in rats, the release of P-glucuronidase from liver lysosomes was assessed ex vivo as a marker for lysosomal membrane integrity. Results, Dexamethasone megadoses significantly inhibited beta -glucuronidase release 10 min post-administration by 38% (3 mg/kg dexamethasone) and 33% (10 mg/kg dexamethasone) at corresponding dexamethasone liver concentrations of 3.9 x 10(-5) mol/kg and 15.1 x 10(-5) mol/kg. respectively. Comparable inhibition of beta -glucuronidase release (34% Cor 3 mg/kg and 38% for 10 mg/kg) was observed 24 h after administration of dexamethasone, although dexamethasone liver concentrations had already declined to 0.09 x 10(-5) mol/kg and 0.19 x 10(-5) mol/kg, respectively. A 2-h oral pretreatment of rats with the glucocorticoid receptor antagonist RU 486 (10 mg/kg) did not alter immediate (10 min) stabilization by dexamethasone: (3 mg/kg), but almost completely prevented lysosomal membrane protection 24 h after dexamethasone injection. Conclusions. Dexamethasone megadoses may preserve lysosomal membrane integrity by a dual action involving both rapid nongenomic effects occurring instantaneously after administration and long-term receptor-dependent genomic events.