Abstract
Background11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activates glucocorticoid locally in liver and fat tissues to aggravate metabolic syndrome. 11β-HSD1 selective inhibitor can be used to treat metabolic syndrome. Curcumin and its derivatives as selective inhibitors of 11β-HSD1 have not been reported.MethodologyCurcumin and its 12 derivatives were tested for their potencies of inhibitory effects on human and rat 11β-HSD1 with selectivity against 11β-HSD2. 200 mg/kg curcumin was gavaged to adult male Sprague-Dawley rats with high-fat-diet-induced metabolic syndrome for 2 months.Results and ConclusionsCurcumin exhibited inhibitory potency against human and rat 11β-HSD1 in intact cells with IC50 values of 2.29 and 5.79 µM, respectively, with selectivity against 11β-HSD2 (IC50, 14.56 and 11.92 µM). Curcumin was a competitive inhibitor of human and rat 11β-HSD1. Curcumin reduced serum glucose, cholesterol, triglyceride, low density lipoprotein levels in high-fat-diet-induced obese rats. Four curcumin derivatives had much higher potencies for Inhibition of 11β-HSD1. One of them is (1E,4E)-1,5-bis(thiophen-2-yl) penta-1,4-dien-3-one (compound 6), which had IC50 values of 93 and 184 nM for human and rat 11β-HSD1, respectively. Compound 6 did not inhibit human and rat kidney 11β-HSD2 at 100 µM. In conclusion, curcumin is effective for the treatment of metabolic syndrome and four novel curcumin derivatives had high potencies for inhibition of human 11β-HSD1 with selectivity against 11β-HSD2.
Highlights
Glucocorticoids (GCs) have a wide range of physiological and pharmacological roles in mammalian functions [1]
In intact CHOP cells transfected with human HSD11B1 and adult rat Leydig cells, curcumin showed inhibitory effects against human and rat 11b-HSD1, with IC50 values of 5.7862.22 mM and 2.2960.69 mM, respectively, indicating that curcumin was slightly potent when the enzyme was assayed in intact cells
The present study demonstrates that curcumin and its derivatives are the selective inhibitors of 11b-HSD1
Summary
Glucocorticoids (GCs) have a wide range of physiological and pharmacological roles in mammalian functions [1]. Intracellular levels of GCs (cortisol in the human or corticosterone, CORT, in the rat) are regulated by 11b-hydroxysteroid dehydrogenase (11bHSD), which has two known isoforms: an NADP+/NADPH dependent 11b-HSD1 oxidoreductase that behaves a primary reductase in the liver and fat tissues (Fig. 1) and an NAD+ dependent 11b-HSD2 [4,5]. 11b-HSD1 knockout mice are resistant to diet-induced obesity and glucose intolerance, and 11bHSD1 over-expression in the fat tissue causes metabolic syndrome [3,7]. We investigated the therapeutic efficacy of curcumin for high-fat-diet (HFD)-induced metabolic syndrome in a rat model, and we screened 12 curcumin analogues (Fig. 2) to test whether these compounds inhibit 11b-HSD1 activity. It is important that 11b-HSD1 inhibitors should not significantly inhibit 11b-HSD2 in order to avoid undesirable sodium retention, hypokalemia, and hypertension
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