Fenofibrate but not fenofibric acid inhibits 11beta-hydroxysteroid dehydrogenase 1 in C2C12 myotubes.
Fibrates and WY-14643 are widely used as lipid-lowering drugs via modulation of peroxisome proliferator-activated receptor alpha (PPAR α) for the treatment of a wide range of metabolic disorders. Here, to address the question whether PPAR α agonists can affect the enzymatic activity of 11beta-hydroxysteroid dehydrogenase1 (11β-HSD1), we tested fibrates and WY-14643 for the inhibition of cellular 11β-HSD1 activity in C2C12 myotubes. Only fenofibrate but not fenofibric acid, an active agonist of PPAR α, exerted a potent inhibitory activity in the cell based assay, showing an IC(50) of 1.6 μM. Furthermore, we also demonstrated that the masking of carboxyl group in fenofibric acid via esterification or amidation was required for the inhibitory potencies of fenofibric acid derivatives against 11β-HSD1. In this presentation, we propose that fenofibrate can display a pharmacodynamic role distinct from fenofibric acid through masking of carboxyl group in fenofibric acid.
Kim
Chi Hyun
CH
Pharmacology Research Center, Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, South Korea.
Ramu
Ravirala
R
Ahn
Jin Hee
JH
Bae
Myung Ae
MA
Cho
Young Sik
YS
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000818:Animals; D002460:Cell Line; D011345:Fenofibrate / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D009132:Muscles / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D047493:PPAR alpha / Q000819:agonists; D011743:Pyrimidines / Q000494:pharmacology
D047493:PPAR alpha; D011743:Pyrimidines; C006253:pirinixic acid; D042842:11-beta-Hydroxysteroid Dehydrogenases; D011345:Fenofibrate