Dexamethasone Megadoses Stabilize Rat Liver Lysosomal Membranes by Non-Genomic and Genomic Effects
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Purpose. Membrane-stabilizing effects may 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 β-glucuronidase from liver lysosomes was assessed ex vivo as a marker for lysosomal membrane integrity.
Results. Dexamethasone megadoses significantly inhibited β-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 × 10−5 mol/kg and 15.1 × 10−5 mol/kg, respectively. Comparable inhibition of β-glucuronidase release (34% for 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 × 10−5 mol/kg and 0.19 × 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.
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