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

Abstract

A rapid screening assay for chemicals inhibiting 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 or type 2 using lysates from stably transfected cells was developed. Here, we tested a series of environmental chemicals for anti-11β-HSD activities. Inhibition of 11β-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 (IC 50 6.3 μM). Abietic acid inhibited both 11β-HSD1 (IC 50 27 μM for reduction and 2.8 μM for oxidation) and 11β-HSD2 (IC 50 12 μM). Our results demonstrate for the first time that flavanone selectively inhibits 11β-HSD1 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 (IC 50 18 and 10 μM) 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 11β-HSD1 and did not inhibit 11β-HSD2. Our results reveal that a variety of environmental compounds exert distinct inhibitory effects on 11β-HSD1 and 11β-HSD2, opening the possibility for selectively modulating local cortisone/cortisol availability in vivo.