Inhibition kinetics of human kidney aldose and aldehyde reductases by aldose reductase inhibitors

Aruni Bhatnagar, Siqi Liu, Ballabh Das, Naseem Ansari, Satish Srivastava

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Abstract

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) bystatil, ICI 105552 [1-(3,4-dichlorobenzyl)-3methyl-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. Ouercetin 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 < ICI 105552 < alrestatin < tolrestat < quercetin < CCA < sorbinil < phenobarbital, and with NADPH as the varied substrate, ICI 105552 < statil < alrestatin < tolrestat < quercetin < CCA < sorbinil < 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.

Original languageEnglish (US)
Pages (from-to)1115-1124
Number of pages10
JournalBiochemical Pharmacology
Volume39
Issue number6
DOIs
StatePublished - Mar 15 1990

Fingerprint

Aldehyde Reductase
Chromones
Kidney
Phenobarbital
Carboxylic Acids
Kinetics
Quercetin
L-glucuronate reductase
NADP
Aldehydes
Substrates
Binding Sites
sorbinil
Substrate Specificity
Acetic Acid
tolrestat
alrestatin
ICI 105552
Molecules
ponalrestat

ASJC Scopus subject areas

  • Pharmacology

Cite this

Inhibition kinetics of human kidney aldose and aldehyde reductases by aldose reductase inhibitors. / Bhatnagar, Aruni; Liu, Siqi; Das, Ballabh; Ansari, Naseem; Srivastava, Satish.

In: Biochemical Pharmacology, Vol. 39, No. 6, 15.03.1990, p. 1115-1124.

Research output: Contribution to journalArticle

Bhatnagar, Aruni ; Liu, Siqi ; Das, Ballabh ; Ansari, Naseem ; Srivastava, Satish. / Inhibition kinetics of human kidney aldose and aldehyde reductases by aldose reductase inhibitors. In: Biochemical Pharmacology. 1990 ; Vol. 39, No. 6. pp. 1115-1124.
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abstract = "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) bystatil, ICI 105552 [1-(3,4-dichlorobenzyl)-3methyl-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. Ouercetin 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 < ICI 105552 < alrestatin < tolrestat < quercetin < CCA < sorbinil < phenobarbital, and with NADPH as the varied substrate, ICI 105552 < statil < alrestatin < tolrestat < quercetin < CCA < sorbinil < 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.",
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AU - Bhatnagar, Aruni

AU - Liu, Siqi

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AU - Ansari, Naseem

AU - Srivastava, Satish

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N2 - 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) bystatil, ICI 105552 [1-(3,4-dichlorobenzyl)-3methyl-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. Ouercetin 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 < ICI 105552 < alrestatin < tolrestat < quercetin < CCA < sorbinil < phenobarbital, and with NADPH as the varied substrate, ICI 105552 < statil < alrestatin < tolrestat < quercetin < CCA < sorbinil < 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.

AB - 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) bystatil, ICI 105552 [1-(3,4-dichlorobenzyl)-3methyl-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. Ouercetin 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 < ICI 105552 < alrestatin < tolrestat < quercetin < CCA < sorbinil < phenobarbital, and with NADPH as the varied substrate, ICI 105552 < statil < alrestatin < tolrestat < quercetin < CCA < sorbinil < 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.

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