Effect of chenodeoxycholic acid on 11β-hydroxysteroid dehydrogenase in various target tissues
Document Type
Article (peer-reviewed)
Publication Date
2004
Abstract
Glucocorticoids are metabolized by isoforms of the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD). There is some controversy concerning the bile acid, chenodeoxycholic acid (CDCA), as a potential endogenously produced inhibitor of 11β-HSD. The present experiments were designed to determine the relative specificity of CDCA for both isoforms of 11β-HSD and to assess the biological relevance of inhibition in vascular tissue. IC50 values (concentrations which inhibit 50% of the enzyme reaction) were calculated using rat liver microsomes as a source of 11β-HSD1 dehydrogenase, Leydig cells for 11β-HSD1 dehydrogenase and reductase, aorta for 11β-HSD1 dehydrogenase and reductase, and sheep kidney for 11β-HSD2 dehydrogenase. In each case, CDCA functioned as a potent inhibitor of 11β-HSD1 dehydrogenase with IC50 values of ranging from 0.2 to 7 μmol/L in contrast to 37 to 200 μmol/L for 11β-HSD1 reductase. CDCA exhibited relatively weak inhibitory activity against 11β-HSD2 from sheep kidney with an IC50 of 70 μmol/L. The effect of CDCA on vascular contraction was studied in aortic rings isolated from Spague-Dawley rats incubated in medium containing corticosterone 10 nmol/L ± CDCA (1 μmol/L) for 24 hours. Rings were stimulated with graded concentrations of phenylephrine (PE) (10 nmol/L, 100 nmol/L, and 1 μmol/L). Rings exposed to corticosterone and CDCA consistently demonstrated a greater contractile response at lower doses of PE (63% at PE 10 nmol/L, P < .001; 20% at PE 100 nmol/L, P < .025; and 10% at PE 1 μmol/L, not significant [NS]) compared to control preparations incubated with cortiosterone alone. These studies demonstrate (1) that CDCA preferentially affects 11β-HSD1 dehydrogenase; (2) CDCA does inhibit 11β-HSD2 dehydrogenase and 11β-HSD1 reductase but only at high(er) concentrations exceeding 70 μmol/L and 37 μmol/L, respectively; and (3) inhibition of 11β-HSD1 dehydrogenase in aortic rings by CDCA (1 μmol/L) enhances the contractile response of corticosterone plus PE.
Recommended Citation
Morris, David J., Graham W. Souness, Syed A. Latif, Matthew P. Hardy, and Andrew S. Brem. 2004. "Effect of chenodeoxycholic acid on 11β-hydroxysteroid dehydrogenase in various target tissues," Metabolism 53(6): 811–816.
DOI
10.1016/j.metabol.2003.12.027
Language
English
https://doi.org/10.1016/j.metabol.2003.12.027