Dexamethasone megadoses stabilize rat liver lysosomal membranes by non-genomic and genomic effects
Dexamethasone megadoses stabilize rat liver lysosomal membranes by non-genomic and genomic effects
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DOI：
10.1023/a:1007652908104
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发表时间：
2000-12-01
影响因子：
3.7
通讯作者：
Hirschelmann, R
中科院分区：
文献类型：
--
作者：
Hinz, B;Hirschelmann, R
目的。在大剂量糖皮质激素治疗过程中，膜稳定作用可能是糖皮质激素作用的一部分。本研究探讨了地塞米松对大鼠肝脏溶酶体膜的作用方式。结果大鼠静脉注射地塞米松后10min，地塞米松剂量分别为3.9×10(-5)和15.1×10(-5)mol/kg时，β-葡萄糖苷酸酶的释放分别被抑制38%(3 mg/kg)和33%(10 mg/kg)。分别进行了分析。虽然地塞米松肝脏浓度已分别降至0.09×10~(-5)m o l/kg和0.19 x 10~(-5)m o l/kg，但24 h后仍可观察到类似的抑制β-葡萄糖苷酸酶释放的作用(34%CoR 3 mg/kg和38%10 m g/kg)。大鼠口服糖皮质激素受体拮抗剂RU 486(10 mg/kg)2 h并不改变地塞米松(3 mg/kg)对溶酶体膜的即刻(10min)稳定作用，但几乎完全阻止了地塞米松注射后24 h的溶酶体膜保护作用。地塞米松巨糖可能通过双重作用维持溶酶体膜的完整性，包括给药后瞬间发生的快速非基因组效应和长期的受体依赖基因组事件。
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.