Genistein inhibits glucocorticoid amplification in adipose tissue by suppression of 11β-hydroxysteroid dehydrogenase type 1

Excess glucocorticoids promote visceral obesity, hyperlipidemia, and insulin resistance. The main regulator of intracellular glucocorticoid levels is 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-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 11 beta-HSD1 in the intralumen of the endoplasmic reticulum, supplies a crucial coenzyme, NADPH, for full reductase activity of 11 beta-HSD1. Therefore, it is possible that inhibition of 11 beta-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 11 beta-HSD1 and H6PD activities within 10 or 20 min, in dose- and time-dependent manners. Inhibition of 11 beta-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 11 beta-HSD1, and its apparent K-m value for 11-dehydrocorticosterone was 0.5 mu M. Genistein also acted as a non-competitive inhibitor of H6PD, and its apparent K-m values for G6P and NADP were 0.9 and 3.3 mu M, respectively. These results suggest that genistein may exert its inhibitory effect by interacting with these enzymes. (C) 2014 Elsevier Inc. All rights reserved.