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

被引:94
作者
Schweizer, RAS [1 ]
Atanasov, AG [1 ]
Frey, BM [1 ]
Odermatt, A [1 ]
机构
[1] Univ Bern, Dept Clin Res, Div Nephrol & Hypertens, CH-3010 Bern, Switzerland
关键词
11 beta-hydroxysteroid dehydrogenase; endocrine disruptor; environmental chemical; glucocorticoid; flavonoid; inhibitor;
D O I
10.1016/j.mce.2003.09.027
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:41 / 49
页数:9
相关论文
共 34 条
[1]   PLASMA-CONCENTRATIONS OF PHYTO-ESTROGENS IN JAPANESE MEN [J].
ADLERCREUTZ, H ;
MARKKANEN, H ;
WATANABE, S .
LANCET, 1993, 342 (8881) :1209-1210
[2]   Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice [J].
Alberts, P ;
Engblom, L ;
Edling, N ;
Forsgren, M ;
Klingström, G ;
Larsson, C ;
Rönquist-Nii, Y ;
Öhman, B ;
Abrahmsén, L .
DIABETOLOGIA, 2002, 45 (11) :1528-1532
[3]   METAANALYSIS OF THE EFFECTS OF SOY PROTEIN-INTAKE ON SERUM-LIPIDS [J].
ANDERSON, JW ;
JOHNSTONE, BM ;
COOKNEWELL, ME .
NEW ENGLAND JOURNAL OF MEDICINE, 1995, 333 (05) :276-282
[4]   Arylsulfonamidothiazoles as a new class of potential antidiabetic drugs.: Discovery of potent and selective inhibitors of the 11β-hydroxysteroid dehydrogenase type 1 [J].
Barf, T ;
Vallgårda, J ;
Emond, R ;
Häggström, C ;
Kurz, G ;
Nygren, A ;
Larwood, V ;
Mosialou, E ;
Axelsson, K ;
Olsson, R ;
Engblom, L ;
Edling, N ;
Rönquist-Nii, Y ;
Öhman, B ;
Alberts, P ;
Abrahmsén, L .
JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (18) :3813-3815
[5]   Anti-inflammatory actions of glucocorticoids: molecular mechanisms [J].
Barnes, PJ .
CLINICAL SCIENCE, 1998, 94 (06) :557-572
[6]   The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11β-hydroxysteroid dehydrogenase:: Potential molecular mechanisms underlying the programming of hypertension in utero [J].
Bertram, C ;
Trowern, AR ;
Copin, N ;
Jackson, AA ;
Whorwood, CB .
ENDOCRINOLOGY, 2001, 142 (07) :2841-2853
[7]   Cytotoxic and endocrine-disrupting potential of atrazine, diazinon, endosulfan, and mancozeb in adrenocortical steroidogenic cells of rainbow trout exposed in vitro [J].
Bisson, M ;
Hontela, A .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 2002, 180 (02) :110-117
[8]   Diethyldithiocarbamate inhibition of galactosamine-induced hepatitis in rats [J].
Disilvestro, RA ;
Rogers, DL ;
Lee, HG .
PHARMACOLOGICAL RESEARCH, 2002, 45 (03) :253-255
[9]   Tumor necrosis factor alpha and interleukin 1 beta enhance the cortisone/cortisol shuttle [J].
Escher, G ;
Galli, I ;
Vishwanath, BS ;
Frey, BM ;
Frey, FJ .
JOURNAL OF EXPERIMENTAL MEDICINE, 1997, 186 (02) :189-198
[10]   Anti-inflammatory activity of abietic acid, a diterpene isolated from Pimenta racemosa var. grissea [J].
Fernández, MA ;
Tornos, MP ;
García, MD ;
de las Heras, B ;
Villar, AM ;
Sáenz, MT .
JOURNAL OF PHARMACY AND PHARMACOLOGY, 2001, 53 (06) :867-872