MOLECULAR PHARMAcoLoGY, 45:797-801 Aldose Reductase-Catalyzed Reduction of Acrolein: Implications

Acrolein, a highly cytotoxic aldehyde, is a metabolic by-product of the antineoplastic agent cyclophosphamide and is responsible for the development of hemorrhagic cystitis, a serious side effect of cyclophosphamide therapy. Aldose reductase (EC 1.1.1.21), a member of the aldo-keto reductase superfamily, catalyzes the NADPH-dependent reduction of acrolein to allyl alcohol (Km 80,sM, kost 87 min1). Aldose reductase is expressed at different levels in individuals. This suggests that individual differences in the reductive metabolism of acrolein may be a determinant of acrolein toxicity. In addition to being a substrate, acrolein also produces a time-dependent 7-20-fold increase in the activity of aldose reductase toward a variety of substrates. This involves initial binding of acrolein to a second site (K5 = 58 zM). Acrolein activation of aldose reductase results not only in higher k1 values for all substrates but also in higher Km values and de-creased catalytic efficiencies. Acrolein activation of aldose reduc