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Pharm Res. 2000 Dec;17(12):1489-93.

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

Author information

1
Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-N├╝rnberg, Germany. hinz@pharmakologie.uni-erlangen.de

Abstract

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 beta-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% 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 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.

PMID:
11303958
DOI:
10.1023/a:1007652908104
[Indexed for MEDLINE]

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