Fenofibrate but not fenofibric acid inhibits 11beta-hydroxysteroid dehydrogenase 1 in C2C12 myotubes

• Published in: Molecular and cellular biochemistry Vol. 344; no. 1-2; pp. 91 - 98
• Main Authors: Kim, Chi Hyun, Ramu, Ravirala, Ahn, Jin Hee, Bae, Myung Ae, Cho, Young Sik
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 01-11-2010; Springer US; Springer; Springer Nature B.V
• Subjects: 11-beta-Hydroxysteroid Dehydrogenases - antagonists & inhibitors; 11Beta-hydroxysteroid dehydrogenase 1; Acids; Animals; Biochemistry; Biomedical and Life Sciences; C2C12; Cardiology; Cell Line; Cellular biology; Cholesterol; Corticosteroids; Enzymatic activity; Enzymes; Fenofibrate; Fenofibrate - pharmacology; Fenofibric acid; Fibric acids; Fluorescence; Homogeneous time resolved fluorescence cortisol assay; Inhibitory Concentration 50; Life Sciences; Lipids; Medical Biochemistry; Metabolic disorders; Mice; Muscles - cytology; Muscles - drug effects; Muscles - enzymology; Oncology; Peroxisome proliferator-activated receptor alpha; Pharmacology; PPAR alpha - agonists; Pyrimidines - pharmacology; Toy industry; Fenofibrate; Fenofibric acid; 11Beta-hydroxysteroid dehydrogenase 1; Peroxisome proliferator-activated receptor alpha; C2C12; Homogeneous time resolved fluorescence cortisol assay
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-010-0532-4

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 IC₅₀ 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.