title: Genistein inhibits glucocorticoid amplification in adipose tissue by suppression of 11β-hydroxysteroid dehydrogenase type 1.
abstract: Excess glucocorticoids promote visceral obesity, hyperlipidemia, and insulin resistance. The main regulator of intracellular glucocorticoid levels is 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive glucocorticoids into bioactive forms such as cortisol in humans and corticosterone in rodents. Hexose-6-phosphate dehydrogenase (H6PD), which is colocalized with 11β-HSD1 in the intralumen of the endoplasmic reticulum, supplies a crucial coenzyme, NADPH, for full reductase activity of 11β-HSD1. Therefore, it is possible that inhibition of 11β-HSD1 will become a considerable medical treatment for metabolic diseases including obesity and diabetes. Genistein, a soy isoflavone, has received attention for its therapeutic potential for obesity, diabetes, and cardiovascular disease, and has been proposed as a promising compound for the treatment of metabolic disorders. However, the mechanisms underlying the pleiotropic anti-obesity effects of genistein have not been fully clarified. Here, we demonstrate that genistein was able to inhibit 11β-HSD1 and H6PD activities within 10 or 20min, in dose- and time-dependent manners. Inhibition of 11β-HSD2 activity was not observed in rat kidney microsomes. The inhibition was not reversed by two estrogen receptor antagonists, tamoxifen and ICI182,780. A kinetic study revealed that genistein acted as a non-competitive inhibitor of 11β-HSD1, and its apparent Km value for 11-dehydrocorticosterone was 0.5μM. Genistein also acted as a non-competitive inhibitor of H6PD, and its apparent Km values for G6P and NADP were 0.9 and 3.3μM, respectively. These results suggest that genistein may exert its inhibitory effect by interacting with these enzymes.
authors.affiliation: Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Japan. Electronic address: t-noriko@kobepharma-u.ac.jp.
authors.forename: Noriko
authors.initials: N
authors.lastname: Tagawa
authors.affiliation: Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kubota
authors.affiliation: Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kato
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000378:metabolism; D041721:3T3-L1 Cells; D000818:Animals; D002237:Carbohydrate Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019833:Genistein / Q000494:pharmacology*; D005938:Glucocorticoids / Q000378:metabolism*; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000201:enzymology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D048789:Phytoestrogens / Q000494:pharmacology*; D017208:Rats, Wistar
chemical_list: D005938:Glucocorticoids; D048789:Phytoestrogens; D019833:Genistein; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D003345:Corticosterone
keywords: 11β-HSD1; Adipocyte; Anti-obesity effect; Genistein; H6PD; Phytoestrogen