Inhibition of aldehyde reductase by aldose reductase inhibitors

Sanai Sato, Peter F Kador

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

A broad group of structurally diverse aldose reductase inhibitors including flavonoids, carboxylic acids and hydantoins, have been examined for their ability to inhibit rat kidney aldehyde reductase (EC 1.1.1.19, EC 1.1.1.20) versus rat lens aldose reductase (EC 1.1.1.21). All aldose reductase. inhibitors examined inhibited aldehyde reductase to some extent both in the reductive reaction as determined with glyceraldehyde as substrate and NADPH as coenzyme, and in the oxidative reaction where l-gulonic acid was oxidized to d-glucuronic acid in the presence of NADP+ Of the inhibitors examined, 2,7-dinuorospirofluorene-9,5′-imidazolidine-2′,4′-dione (A11576) was the most potent inhibitor requiring only concentrations in the 10-8 M range to inhibit 50% of the in vitro activity of rat kidney aldehyde reductase (ic50 value), whereas 3-dioxo-1-H-benz[de]isoquinoline-2(3H)-acetic acid (alrestatin) was the least potent inhibitor requiring concentrations in the 10-5 M range. Both the reductive and oxidative steps appeared equally inhibited by these aldose reductases inhibitors. Moreover, all compounds appeared to inhibit either crude or highly purified rat kidney aldehyde reductase to essentially the same extent. Marked differences in the selectivity of these inhibitors, expressed as the ratio of ic50 values for rat kidney aldehyde reductase versus rat lens aldose reductase with glyceraldehyde as substrate, were observed with selectivity for aldose reductase ranging from ca. 2-fold for A11576 to 119-fold for 3-(4-bromo-2-nuorobenzyl-4-oxo-3-phthalazine-1-ylacetic acid (Ponalrestat). Kinetic and competition studies suggest that these inhibitors interact with aldehyde reductase at a common site that is not identical to either the substrate or nucleotide binding site. These results suggest that the inhibitor binding sites of rat kidney aldehyde reductase and aldose reductase contain several common characteristics.

Original languageEnglish (US)
Pages (from-to)1033-1042
Number of pages10
JournalBiochemical Pharmacology
Volume40
Issue number5
DOIs
StatePublished - Sep 1 1990

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Aldehyde Reductase
Rats
Kidney
Glyceraldehyde
glucuronolactone reductase
L-glucuronate reductase
NADP
Lenses
Inhibitory Concentration 50
Substrates
Binding Sites
Hydantoins
Glucuronic Acid
Coenzymes
Carboxylic Acids
Flavonoids
Acetic Acid

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Inhibition of aldehyde reductase by aldose reductase inhibitors. / Sato, Sanai; Kador, Peter F.

In: Biochemical Pharmacology, Vol. 40, No. 5, 01.09.1990, p. 1033-1042.

Research output: Contribution to journalArticle

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