Fibrates inhibit aldose reductase activity in the forward and reverse reactions.
Fibrates such as bezafibrate, gemfibrozil, clofibric acid, ciprofibrate and fenofibrate, are ligands for peroxisome proliferator-activated receptor alpha (PPARalpha), and are used as therapeutic agents in the treatment of hyperlipidemia. Synthesis and accumulation of sorbitol in cells due to aldose reductase (AR) activity is implicated in secondary diabetic complications. In pursuit of finding a lead compound identification to design an effective AR inhibitor employing fragment-based design-like approach, we found that this class of compounds and their nearest neighbors could inhibit AR. Bezafibrate and gemfibrozil displayed a mixed non-competitive inhibition pattern in the glyceraldehyde reduction activity and pure non-competitive inhibition pattern in the benzyl alcohol oxidation activity of AR. Clofibric acid, ciprofibrate and fenofibrate showed pure non-competitive inhibition patterns in the forward reaction. In the reverse reaction, clofibric acid displayed a non-competitive inhibition pattern while ciprofibrate and fenofibrate displayed competitive inhibition patterns. This finding reveals for the first time a novel attribute of the fibrates in the regulation of AR activity and may be useful as lead compounds to control the function of AR in the progression and treatment of secondary diabetic complications in addition to other clinical conditions. Alternatively, these findings demonstrate that AR plays a significant role in the fibrate metabolism under various scenarios.
Balendiran
Ganesaratnam K
GK
Division of Immunology, Beckman Research Institute of the City of Hope National Medical Center, 1450 E. Duarte Road, Duarte, CA 91010, USA. gbalendiran@coh.org
Rajkumar
Balakrishnan
B
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019905:Benzyl Alcohol / Q000378:metabolism; D002995:Clofibric Acid / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013379:Substrate Specificity
D000960:Hypolipidemic Agents; D002995:Clofibric Acid; D000449:Aldehyde Reductase; D019905:Benzyl Alcohol