Abstract
The microsomal enzyme 11β-hydroxysteroid deydrogenase type 1 (11β-HSD1) catalyzes the interconversion of glucocorticoid receptor-inert cortisone to receptor- active cortisol, thereby acting as an intracellular switch for regulating the access of glucocorticoid hormones to the glucocorticoid receptor. There is strong evidence for an important aetiological role of 11β-HSD1 in various metabolic disorders including insulin resistance, diabetes type 2, hypertension, dyslipidemia and obesity. Hence, modulation of 11β-HSD1 activity with selective inhibitors is being pursued as a new therapeutic approach for the treatment of the metabolic syndrome. Since tea has been associated with health benefits for thousands of years, we sought to elucidate the active principle in tea with regard to diabetes type 2 prevention. Several teas and tea specific polyphenolic compounds were tested for their possible inhibition of cortisone reduction with human liver microsomes and purified human 11β-HSD1. Indeed we found that tea extracts inhibited 11β-HSD1 mediated cortisone reduction, where green tea exhibited the highest inhibitory potency with an IC50 value of 3.749 mg dried tea leaves per ml. Consequently, major polyphenolic compounds from green tea, in particular catechins were tested with the same systems. (−)-Epigallocatechin gallate (EGCG) revealed the highest inhibition of 11β-HSD1 activity (reduction: IC50 = 57.99 µM; oxidation: IC50 = 131.2 µM). Detailed kinetic studies indicate a direct competition mode of EGCG, with substrate and/or cofactor binding. Inhibition constants of EGCG on cortisone reduction were Ki = 22.68 µM for microsomes and Ki = 18.74 µM for purified 11β-HSD1. In silicio docking studies support the view that EGCG binds directly to the active site of 11β-HSD1 by forming a hydrogen bond with Lys187 of the catalytic triade. Our study is the first to provide evidence that the health benefits of green tea and its polyphenolic compounds may be attributed to an inhibition of the cortisol producing enzyme 11β-HSD1.
Highlights
Tea (Camellia sinensis) is the second most widely consumed beverage in the world after water [1] and has been cultivated for thousands of years due to its medicinal benefits and general health promotion purposes.The tea plant is naturally occurring in South China, but is nowadays cultivated in many other regions of the major tea producing countries in the world, like India, Japan, Sri Lanka, Indonesia and Kenia
Enzyme assay In terms of 11b-HSD1 reductase activity, inhibition analysis was performed as follows: 50 ml of tea extract were added to a mixture containing 400 mM cortisone, 0.8 mM NADPH solution in 100 mM phosphate buffer pH 7.4
Inhibition of 11b-HSD1 activity was assessed by determining cortisol yields after 3 h incubation at 37uC with equal volumes of green, black and white tea infusions (100 mg tea per ml; prepared as described above)
Summary
Tea (Camellia sinensis) is the second most widely consumed beverage in the world after water [1] and has been cultivated for thousands of years due to its medicinal benefits and general health promotion purposes.The tea plant is naturally occurring in South China, but is nowadays cultivated in many other regions of the major tea producing countries in the world, like India, Japan, Sri Lanka, Indonesia and Kenia. Enzyme assay In terms of 11b-HSD1 reductase activity, inhibition analysis was performed as follows: 50 ml of tea extract were added to a mixture containing 400 mM cortisone, 0.8 mM NADPH solution in 100 mM phosphate buffer pH 7.4. The type of inhibition was tested with both human liver microsomes (218 mg) and purified 11b-HSD1 (16.4 mg).
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