| 8149893 |
Kanekal S, Kehrer JP: Metabolism of cyclophosphamide by lipoxygenases. . Drug Metab Dispos. 1994 Jan-Feb;22(1):74-8.
Cyclophosphamide (CP) can be cooxidized by several peroxidases. A number of xenobiotics also undergo cooxidation during metabolism of unsaturated fatty acids by lipoxygenases. The current study examined linoleic acid-dependent cooxidation of CP by soybean lipoxygenase and rabbit 15-lipoxygenase. Incubations of CP (0-5 mM) with soybean lipoxygenase (0-1 x 10 (4) units) and linoleic acid (0-5 mM) resulted in the generation of acrolein, an easily detected breakdown product of the initial unstable hydroxylated CP metabolite. Acrolein formation was dependent on time and concentrations of the enzyme, linoleic acid, and CP. The formation of acrolein was complete by 3 min and was favored at pHs above 7. The lipoxygenase inhibitors BW755C (0.1 mM), BWA4C (0.1 mM), and phenidione (0.01 mM) significantly inhibited the metabolism of CP to acrolein by 92, 66, and 57%, respectively. Vitamin E (0.1 mM), superoxide dismutase (10 units), and nordihydroguaiaretic acid (0.1 mM) significantly decreased acrolein generation by 74, 76, and 77%, respectively. Glutathione (1 mM) significantly decreased measurable acrolein by 80%, perhaps by binding to this reactive aldehyde. One mM cysteine, mercaptoethane sulfonic acid, glutathione disulfide, or albumin also decreased measurable acrolein (16-36%), but significantly less efficiently than glutathione. Incubation of rabbit leukocyte 15-lipoxygenase with linoleic acid and CP also resulted in the generation of acrolein. These results indicate that lipoxygenases can cooxidize CP. The inhibitory effects of antioxidants suggest that this catalysis may involve free radicals. |
72(0,2,3,7) |