In vivo and in vitro effects of glucocorticosteroids on arachidonic acid metabolism and monocyte function in nonasthmatic humans.
Glucocorticosteroids are used as anti-inflammatory agents in a range of diseases, however, their mechanism of action is unknown. Recently, inhibition of arachidonic acid metabolism has been suggested as one possible mechanism of action. A series of experiments were undertaken in nonasthmatic humans to examine the effects of oral prednisolone and dexamethasone and inhaled budesonide on the excretion of the urinary leukotriene E4 (LTE4), an established marker of total body leukotriene generation in vivo. In addition, the effect of the drugs on the in vitro and ex-vivo function of monocytes was examined. In vitro dexamethasone greater than 10(-8) M inhibited the thromboxane A2 (TxA2) release from human monocytes, an effect which recovered within 24 h. In vivo, neither inhaled budesonide (1.6 mg.day-1 for 7 days), nor a standard therapeutic dose of oral prednisolone (30 mg.day-1 for 3 days), nor high doses of oral dexamethasone (8 mg.day-1 for 2 days) altered the excretion of urinary LTE4, despite the latter completely suppressing endogenous cortisol production. The ex-vivo zymosan stimulated release of TxA2 release from monocytes was not altered by the standard dose prednisolone, but was reduced by high dose dexamethasone and inhaled budesonide. This study shows that high doses of systemic steroids have little effect on arachidonic acid metabolism in normal nonasthmatic humans. Inhaled budesonide, however, does reduce arachidonic acid metabolism in circulating monocytes, presumably by affecting these cells during their passage through the lung.
Manso
G
G
Dept of Clinical Pharmacology, Royal Postgraduate Medical School, London, UK.
Baker
A J
AJ
Taylor
I K
IK
Fuller
R W
RW
D000287:Administration, Topical; D000328:Adult; D000336:Aerosols; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism*; D019819:Budesonide; D003907:Dexamethasone / Q000494:pharmacology*; D004311:Double-Blind Method; D004341:Drug Evaluation; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D066298:In Vitro Techniques; D017999:Leukotriene E4; D008297:Male; D009000:Monocytes / Q000187:drug effects*; D011239:Prednisolone / Q000494:pharmacology*; D011282:Pregnenediones / Q000494:pharmacology*; D013189:SRS-A / Q000031:analogs & derivatives* / Q000652:urine; D013931:Thromboxanes / Q000378:metabolism
D000336:Aerosols; D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D011282:Pregnenediones; D013189:SRS-A; D013931:Thromboxanes; D016718:Arachidonic Acid; D019819:Budesonide; D017999:Leukotriene E4; D003907:Dexamethasone; D011239:Prednisolone