Aldose reductase-catalyzed reduction of acrolein: implications in cyclophosphamide toxicity

• Published in: Molecular pharmacology Vol. 45; no. 4; pp. 797 - 801
• Main Authors: KOLB, N. S, HUNSAKER, L. A, JAGT, D. L
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.04.1994
• Subjects: Acrolein - metabolism; Aldehyde Reductase - metabolism; Biological and medical sciences; Cyclophosphamide - toxicity; Drug toxicity and drugs side effects treatment; Enzyme Activation; Humans; Imidazoles - pharmacology; Imidazolidines; Medical sciences; Muscles - enzymology; Oxidation-Reduction; Pharmacology. Drug treatments; Phthalazines - pharmacology; Substrate Specificity; Toxicity: urogenital system; Antineoplastic agent; Acrolein; Enzymatic activity; Enzyme; Toxicity; Aldehyde reductase; Oxidoreductases; Mechanism of action
• ISSN: 0026-895X; 1521-0111

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 microM, kcat = 87 min-1). 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 (Ks = 58 microM). Acrolein activation of aldose reductase results not only in higher kcat values for all substrates but also in higher Km values and decreased catalytic efficiencies. Acrolein activation of aldose reductase reduces its affinity for aldose reductase inhibitors.