Curcumin as a potent and selective inhibitor of 11β-hydroxysteroid dehydrogenase 1: improving lipid profiles in high-fat-diet-treated rats

PLoS One. 2013;8(3):e49976. doi: 10.1371/journal.pone.0049976. Epub 2013 Mar 22.

Abstract

Background: 11β-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.

Methodology: Curcumin 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 conclusions: Curcumin 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / antagonists & inhibitors
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / metabolism
  • Animals
  • Blood Glucose / drug effects
  • Cholesterol / blood
  • Curcumin / pharmacology
  • Curcumin / therapeutic use*
  • Diet, High-Fat / adverse effects*
  • Humans
  • Kidney / enzymology
  • Leydig Cells / drug effects
  • Leydig Cells / metabolism
  • Lipoproteins, LDL
  • Male
  • Metabolic Syndrome / blood
  • Metabolic Syndrome / chemically induced
  • Metabolic Syndrome / drug therapy*
  • Microsomes / enzymology
  • Rats
  • Rats, Sprague-Dawley
  • Triglycerides / blood

Substances

  • Blood Glucose
  • Lipoproteins, LDL
  • Triglycerides
  • Cholesterol
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2
  • Curcumin

Grant support

This work was partially supported by the Wenzhou Science & Technology Funding (Y20090003 to R.S.G. 2008H0121 to HYZ) and Natural Science Foundation of China (NSFC) (81102149 to YHC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.