Inhibition kinetics of human kidney aldose and aldehyde reductases by aldose reductase inhibitors.
Kinetic patterns of inhibition of homogenous human kidney aldose reductase (AR, EC 1.1.1.21) and aldehyde reductase II (AR II, EC 1.1.1.19) by statil, ICI 105552 [1-(3,4-dichlorobenzyl)-3-methyl-1,2-dihydro-2-oxoquinol-4-yl acetic acid], tolrestat, alrestatin, chromone carboxylic acid (CCA), quercetin, phenobarbital and sorbinil were studied. On the basis of the kinetic nature of inhibition, the inhibitors were classified into four distinct categories. For aldose reductase, sorbinil and phenobarbital were noncompetitive (NC; category I) and CCA and alrestatin were uncompetitive (UC; category II) to both the aldehyde substrate and NADPH. Quercetin and ICI 105552 were NC to the aldehyde and UC to NADPH (category III) and tolrestat and statil were UC to the aldehyde and NC to NADPH (category IV). For AR II, sorbinil and alrestatin were category I inhibitors, ICI 105552 and statil belong to category II, phenobarbital, tolrestat and CCA to category III, and quercetin to category IV. To determine the specificity of inhibition, the ratios of the inhibition constants (Kii) for AR and AR II were calculated. A lower ratio indicates greater specificity. With aldehyde as the varied substrate the specificity ratios were: statil less than ICI 105552 less than alrestatin less than tolrestat less than quercetin less than CCA less than sorbinil less than phenobarbital, and with NADPH as the varied substrate, ICI 105552 less than statil less than alrestatin less than tolrestat less than quercetin less than CCA less than sorbinil less than phenobarbital. For AR, double-inhibition plots generated for one inhibitor from each kinetic category versus sorbinil showed that AR inhibitors of categories I-III bind to the same site on the protein molecule as sorbinil. However, tolrestat seemed to bind to a site different from the sorbinil binding site. For AR II, inhibitors from all the four categories appeared to bind to the same inhibitor binding site.
Bhatnagar
A
A
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston 77550.
Liu
S Q
SQ
Das
B
B
Ansari
N H
NH
Srivastava
S K
SK
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D002237:Carbohydrate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D007546:Isoquinolines / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology*; D007700:Kinetics; D009281:Naphthalenes / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D010793:Phthalazines / Q000494:pharmacology; D011794:Quercetin / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D013379:Substrate Specificity; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
D000447:Aldehydes; D002867:Chromones; D007093:Imidazoles; D048289:Imidazolidines; D007546:Isoquinolines; D009281:Naphthalenes; D010793:Phthalazines; D015363:Quinolones; C040550:tolrestat; C042829:ponalrestat; C026488:7-hydroxy-4-oxo-4H-chromen-2-carboxylic acid; C016212:alrestatin; C033661:ICI 105552; D011794:Quercetin; D002237:Carbohydrate Dehydrogenases; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase; C020843:gulonate dehydrogenase; C026411:sorbinil; D010634:Phenobarbital