Specific inhibitory effect of some natural products toward aldose reductase

Abstract

Aldose reductase (AR) catalyzes reduction of carbonyl compounds including glucose. In hyperglycemic conditions, AR reduces glucose into sorbitol, which eventually causes diabetes complication. Therefore, there were many attempts to develop AR inhibitors (ARI) as a medication for diabetes complication. However, effectiveness of these trials has been reported to be doubtful. Considering that AR is a member of aldo-keto reductase (AKR) family of which members are thought to be involved in detoxifying various reactive aldehydes, treatment of ARI might also inhibit other AKR family members resulting in side effects. Here, we have cloned and characterized three members of AKR family - AR, aldose reductase-like protein (ARL), and aldehyde reductase (ALR) - to determine the specificity of ARIs toward these AKR members. Using this set of enzymes, inhibition ability of ARI candidates derived from plants, butein, quercitrin, TO 2e2, and TO EA3S, was examined. First, concentrations of the ARIs to inhibit 50% of enzyme activity (IC50) were determined for each compound. Using these IC50 values, specificity indexes (SI) of ARIs inhibiting these enzymes were calculated by dividing IC50 for ARL and ALR by IC50 for AR for each compound. As a result, butein showed the least specific inhibition toward AR and quercitrin showed the most specific inhibition toward AR.