Dexamethasone megadoses stabilize rat liver lysosomal membranes by non-genomic and genomic effects.
OBJECTIVE
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.
Hinz
B
B
Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nürnberg, Germany. hinz@pharmakologie.uni-erlangen.de
Hirschelmann
R
R
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003907:Dexamethasone / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005260:Female; D016678:Genome; D005966:Glucuronidase / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008247:Lysosomes / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D015735:Mifepristone / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000893:Anti-Inflammatory Agents; D006727:Hormone Antagonists; D015735:Mifepristone; D003907:Dexamethasone; D005966:Glucuronidase