Inhibitors of Aldose Reductase

Abstract Aldose reductase (AR) inhibitors are designed to interfere with the initiation and early development of secondary complications of chronic diabetes mellitus. The concept was deduced from the insight that, in diabetic tissues with insulin-independent glucose uptake, excess glucose is metabolized via the polyol (sorbitol) pathway. The polyol pathway comprises two enzymatic reactions: in tandem, glucose is reduced to sorbitol by AR using NADPH, and sorbitol is oxidized to fructose by sorbitol dehydrogenase using NAD+ (Fig. 16.1). According to Vander Jagt et al. (1990), AR functions as an NADPH-binding protein, thus facilitating oxidation of NADPH. In contrast with other aldehyde or ketone reductases, such as lactate dehydrogenase (LDH) or alcohol dehydrogenase (ADH), AR is almost exclusively a ‘one-way catalyst, with a ratio of catalytic efficiency for the forward versus the reverse reaction that is 1000-100 000 times higher than that for either LDH or ADH (Grimshaw 1991).