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Curcumin and its derivative as novel 11beta‐HSD1 modulators to treat glucocorticoid excess syndrome
Author(s) -
Liang Guang,
Li Xiaokun
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.749.6
Glucocorticoid (GC) excess is associated with type ‐2 diabetes and hypogonadism. The oxidoreductase 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) mainly catalyzes the intracellular regeneration of active GCs from inert inactive 11‐keto forms in liver, adipose tissue and brain, amplifying local GC action. Inhibition of 11β‐HSD1 offers a potential therapy to attenuate the type 2 diabetes. However, the current selective 11β‐HSD1 inhibitors inhibit the bi‐directional activities of 11β‐HSD1, both 11β‐HSD1 reductase (major) and oxidase (minor). Here we report that curcumin and its derivative (B06) have novel properties by competitively suppressing 11β‐HSD1 reductase activity while increasing its oxidase activity through increasing SER luminal cofactor NADP+ levels after suppressing hexose‐6‐phosphate dehydrogenase activity which plays a critical role in 11β‐HSD1 directionality. The IC50 of inhibiting 11β‐HSD1 reductase activity was 3 ± 0.2 μM and 100 nM, and the EC50 of stimulating oxidase activity was 2.04 ± 0.2 μM and 86 ± 0.2 nM by curcumin and B6, respectively, in rat Leydig cells. Curcumin inhibited 11β‐HSD2 with IC50s of 13 μM for rat kidney, while B6 did not. Oral administration of curcumin (100 to 200 mg/kg/day) or B6 (1–4mg/kg/day) for three days completely prevented the decreases of serum testosterone levels induced by restraint stress in male rats, and oral administration of B6 (4 mg/kg/day) for 2 months also prevented the formation of fatty liver and increase of serum glucose and lipid induced by high‐fat diet. Furthermore, db/db and normal C57BL/6J mice were orally administered B06 (0.8 mg/kg/d, daily). The results in serum glucose, cholesterol, triglycerides, oral glucose tolerance tests and insulin tolerance tests support that B06 lower blood glucose levels and improve insulin sensitivity in mouse models of type 2 diabetes. The present study demonstrated novel 11β‐HSD1 modulators targeted both 11β‐HSD1 oxidase and reductase