Inhibition of NADPH-cytochrome P450 reductase by cyclophosphamide and its metabolites |
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| Authors: | A J Marinello M J Berrigan R F Struck F P Guengerich H L Gurtoo |
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| Affiliation: | 1. Department of Experimental Therapeutics Roswell Park Memorial Institute Buffalo, NY 14263 USA;2. Grace Cancer Drug Center Roswell Park Memorial Institute Buffalo, NY 14263 USA;3. Southern Research Institute Birmingham, Ala. 35205 USA;4. Department of Biochemistry Vanderbilt University Nashville, TN 37232 USA;5. Center for Environmental Toxicology Vanderbilt University Nashville, TN 37232 USA |
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| Abstract: | Cyclophosphamide (CP) administration to rats produced a dose-dependent loss of hepatic NADPH-cytochrome-P450 reductase and microsomal mixed function oxidase (MFO) activities. CP, its metabolites (acrolein, phosphoramide mustard, 4-keto CP and nor-nitrogen mustard) and Ifosfamide, which is an analog of CP, were tested for their effects on the reductase activity. Only acrolein produced a significant loss of the reductase (66%). This loss of activity could be prevented by the presence of cysteine in the incubation mixture. Acrolein also produced a dose dependent loss of the activity when incubated with the purified reductase. These data suggest that CP-induced loss of the reductase results from interaction between CP metabolite acrolein and critical sulfhydryl groups in the reductase. |
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| Keywords: | To whom requests for reprints should be addressed. |
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