Intrinsic inhibition of aldose reductase.
The development of aldose reductase inhibitors for the treatment of diabetic complications, such as cataract and retinopathy, has been of intense interest in the pharmaceutical community for the last 20 years. To date, aldose reductase inhibitors have been synthetically developed from leads obtained from in vitro screening studies. Recently, we have observed that mammalian tissues contain intrinsic inhibitors of aldose reductase, which may be used as potential drugs for treating diabetic complications with potentially less side effects than synthetic aldose reductase inhibitors. Intrinsic inhibitor(s) of aldose reductase have been observed in the methanolic extracts from rat and human kidneys and bovine lenses that were subjected to a number of chromatographic techniques, including counter current chromatography, flash chromatography, gel filtration and high pressure liquid chromatography. This inhibition results from a direct interaction between the inhibitor and enzyme. The intrinsic inhibitor, present in the lipophilic fraction of human kidney and bovine lens extracts, can easily penetrate into the lens to inhibit sugar alcohol formation. Intraperitoneal injection of partially purified bovine lens extract inhibited lens polyol formation in young rats fed 50% galactose diet.
Kador
P F
PF
Laboratory of Ocular Therapeutics, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1850, USA. kador@helix.nih.gov
Sun
G
G
Rait
V K
VK
Rodriguez
L
L
Ma
Y
Y
Sugiyama
K
K
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002417:Cattle; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D004376:Galactitol / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000737:chemistry / Q000201:enzymology*; D007908:Lens, Crystalline / Q000737:chemistry / Q000201:enzymology*; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013012:Sorbitol / Q000378:metabolism
D004791:Enzyme Inhibitors; D004376:Galactitol; D013012:Sorbitol; D000449:Aldehyde Reductase