A rapid screening assay for inhibitors of 11β-hydroxysteroid dehydrogenases (11β-HSD):: flavanone selectively inhibits 11β-HSD1 reductase activity

A rapid screening assay for chemicals inhibiting I I p-hydroxysteroid dehydrogenase (11beta-HSD) type I or type 2 using lysates from stably transfected cells was developed. Here, we tested a series of environmental chemicals for anti-11beta-HSD activities. Inhibition of 11beta-HSD2, which may cause cortisol-dependent activation of the mineralocorticoid receptor with sodium retention and hypertension, was observed for several compounds, with diethylcarbamate being the most potent inhibitor (IC50 6.3 muM). Abietic acid inhibited both 11beta-HSD1 (IC50 27 muM for reduction and 2.8 muM for oxidation) and 11beta-HSD2 (IC50 12 muM). Our results demonstrate for the first time that flavanone selectively inhibits 11beta-HSD 1 reductase activity: this enzyme being considered as essential for the local activation of glucocorticoids and representing a potential target for the therapeutic treatment of diabetes type 2. Flavanone and 2'-hydroxyflavanone efficiently inhibited reductive (IC50 18 and 10 muM) but not oxidative activity. We observed a reduced inhibitory effect of hydroxylated flavanone derivatives and of flavones containing a double-bond between atom C2 and C3. Flavanone was specific for 11beta-HSD1 and did not inhibit 11beta-HSD2. Our results reveal that a variety of environmental compounds exert distinct inhibitory effects on 11beta-HSD1 and 11beta-HSD2, opening the possibility for selectively modulating local cortisone/cortisol availability in vivo. (C) 2003 Elsevier Ireland Ltd. All rights reserved.