Potential regulation of inflammation in the lung by local metabolism of hydrocortisone.
Human lung tissue converts hydrocortisone to cortisone by the action of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). Since cortisone is inactive as an antiinflammatory steroid, the action of this enzyme may regulate the local antiinflammatory effects of glucocorticoids in the lung. Minced human lung tissue (100 mg in 500 microliters medium) metabolized approximately 50% of added [3H]hydrocortisone within 2 h in most lung specimens. Metabolism was linear during this period and was found to occur over a broad range of concentrations of hydrocortisone (1 to 1,000 nM). Metabolism of hydrocortisone was not observed in minced pulmonary blood vessels or airways (2 to 3 mm), and pleura (containing some adherent parenchyma) had less activity than parenchyma. Cultured human tracheal epithelial cells metabolized hydrocortisone, while umbilical vein endothelial cells did not. Since glycyrrhizin, glycyrrhetinic acid, and carbenoxolone have antiinflammatory properties and have recently been shown to interfere with steroid metabolism in renal tissues, their effects on 11 beta-HSD in human lung tissue have been tested. Conversion of hydrocortisone to cortisone by lung tissue was inhibited by glycyrrhetinic acid (IC50, approximately 2.5 x 10(-8) M) and carbenoxolone (1.5 x 10(-7) M), but not glycyrrhizin (greater than 10(-5) M). It is proposed that inhibition of the metabolism of hydrocortisone by 11 beta-HSD may partially explain the known antiinflammatory actions of orally administered glycyrrhetinic acid and carbenoxolone and that intrapulmonary administration of these compounds may produce antiinflammatory effects targeted to the lung.
Schleimer
R P
RP
Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224.
D042842:11-beta-Hydroxysteroid Dehydrogenases; D002229:Carbenoxolone / Q000494:pharmacology; D002478:Cells, Cultured; D003348:Cortisone / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D019695:Glycyrrhizic Acid; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D007700:Kinetics; D008168:Lung / Q000098:blood supply / Q000378:metabolism*; D010994:Pleura / Q000378:metabolism; D014132:Trachea / Q000378:metabolism
D019695:Glycyrrhizic Acid; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D002229:Carbenoxolone; D006034:Glycyrrhetinic Acid; D003348:Cortisone; D006854:Hydrocortisone