Inhibition of Human Brain Aldose Reductase and Hexonate Dehydrogenase by Alrestatin and Sorbinil

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Abstract
Human brain aldose reductase and hexonate dehydrogenase are inhibited by alrestatin (AY 22,284) and sorbinil (CP 45,634). Inhibition by alrestatin is noncompetitive for both enzymes, and slightly stronger for hexonate dehydrogenase (KI values 52-250 μM) than for aldose reductase (KI values 170-320 μM). Sorbinil inhibits hexonate dehydrogenase far more potently than aldose reductase, KI values being 5 μM for hexonate dehydrogenase and 150 μM for aldose reductase. The inhibition of hexonate dehydrogenase by sorbinil is noncompetitive with respect to both aldehyde and NADPH substrates, and is thus kinetically similar to the inhibition by alrestatin. However, sorbinil inhibition of aldose reductase is uncompetitive with respect to glyceraldehyde and noncompetitive with NADPH as the varied substrate. Inhibition of human brain aldose reductase by these two inhibitors is much less potent than that reported for the enzyme from other sources.