Inhibition of NADPH-cytochrome P450 reductase by cyclophosphamide and its metabolites

• Published in: Biochemical and biophysical research communications Vol. 99; no. 2; pp. 399 - 406
• Main Authors: Marinello, A.J., Berrigan, M.J., Struck, R.F., Guengerich, F.P., Gurtoo, H.L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31.03.1981
• Subjects: Animals; Aryl Hydrocarbon Hydroxylases - metabolism; Cyclophosphamide - analogs & derivatives; Cyclophosphamide - pharmacology; Cytochrome P-450 Enzyme System - metabolism; Male; Microsomes, Liver - enzymology; Mixed Function Oxygenases - antagonists & inhibitors; NADPH-Ferrihemoprotein Reductase - antagonists & inhibitors; Rats; Structure-Activity Relationship
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/0006-291X(81)91759-9

Cyclophosphamide (CP) administration to rats produced a dose-dependent loss of hepatic NADPH-cytochrome-P450 reductase and microsomal mixed function oxidase (MFO) activities. In vitro 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.