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

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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. 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.

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  • Potential biological functions of cytochrome P450 reductase-dependent enzymes in small intestine: Novel link to expression of major histocompatibility complex class II genes

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    This finding, which defines a new physiological/pathological role of intestinal POR/P450 enzymes in modulating the expression of regulators of intestinal immunity, may have important clinical significance. POR is a direct target of inhibition by various drugs and other xenobiotic compounds (e.g. cyclophosphamide (57), ellipticine (58), and cadmium (59)). Furthermore, numerous genetic polymorphisms of the human POR gene that affect either POR expression or POR activity have been identified (60–63).

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This work was supported by USPHS Grants CA-23634 (HLG, RFS) and CA-13038 from the National Cancer Institute, Bethesda, MD.

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