Effect of chenodeoxycholic acid on 11beta-hydroxysteroid dehydrogenase in various target tissues.
Glucocorticoids are metabolized by isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD). There is some controversy concerning the bile acid, chenodeoxycholic acid (CDCA), as a potential endogenously produced inhibitor of 11beta-HSD. The present experiments were designed to determine the relative specificity of CDCA for both isoforms of 11beta-HSD and to assess the biological relevance of inhibition in vascular tissue. IC(50) values (concentrations which inhibit 50% of the enzyme reaction) were calculated using rat liver microsomes as a source of 11beta-HSD1 dehydrogenase, Leydig cells for 11beta-HSD1 dehydrogenase and reductase, aorta for 11beta-HSD1 dehydrogenase and reductase, and sheep kidney for 11beta-HSD2 dehydrogenase. In each case, CDCA functioned as a potent inhibitor of 11beta-HSD1 dehydrogenase with IC(50) values of ranging from 0.2 to 7 micromol/L in contrast to 37 to 200 micromol/L for 11beta-HSD1 reductase. CDCA exhibited relatively weak inhibitory activity against 11beta-HSD2 from sheep kidney with an IC(50) of 70 micromol/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 micromol/L) for 24 hours. Rings were stimulated with graded concentrations of phenylephrine (PE) (10 nmol/L, 100 nmol/L, and 1 micromol/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 micromol/L, not significant [NS]) compared to control preparations incubated with cortiosterone alone. These studies demonstrate (1) that CDCA preferentially affects 11beta-HSD1 dehydrogenase; (2) CDCA does inhibit 11beta-HSD2 dehydrogenase and 11beta-HSD1 reductase but only at high(er) concentrations exceeding 70 micromol/L and 37 micromol/L, respectively; and (3) inhibition of 11beta-HSD1 dehydrogenase in aortic rings by CDCA (1 micromol/L) enhances the contractile response of corticosterone plus PE.
Morris
David J
DJ
The Miriam Hospital and Rhode Island Hospital, Brown University Medical School, Providence, RI, USA.
Souness
Graham W
GW
Latif
Syed A
SA
Hardy
Matthew P
MP
Brem
Andrew S
AS
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007985:Leydig Cells / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D002635:Chenodeoxycholic Acid; D010656:Phenylephrine; D042842:11-beta-Hydroxysteroid Dehydrogenases