Activation of the anti-cancer drug ifosphamide by rat liver microsomal P450 enzymes.
The NADPH-dependent metabolism of ifosphamide catalyzed by rat liver microsomes was investigated in order to identify individual P450 enzymes that activate this anti-cancer drug and to ascertain their relationship to the P450 enzymes that activate the isomeric drug cyclophosphamide. Pretreatment of rats with phenobarbital or clofibrate increased by up to 8-fold the activation of both ifosphamide and cyclophosphamide catalyzed by isolated liver microsomes. Studies using P450 form-selective inhibitory antibodies demonstrated that constitutively expressed P450s belonging to subfamily 2C (forms 2C11/2C6) make significant contributions to the activation of both oxazaphosphorines in uninduced male rat liver microsomes, while the phenobarbital-inducible P450 2B1 was shown to be a major catalyst of these activations in phenobarbital-induced microsomes. Pretreatment of rats with dexamethasone increased liver microsomal activation of ifosphamide approximately 6-fold without a corresponding effect on cyclophosphamide activation rates. Ifosphamide activation catalyzed by dexamethasone-induced liver microsomes was minimally inhibited by anti-P450 2B or anti-P450 2C antibodies, but was selectively inhibited by anti-P450 3A antibodies. Selective inhibition of liver microsomal ifosphamide activation was also effected by the macrolide antibiotic triacetyloleandomycin, an inhibitor of several dexamethasone-inducible 3A P450s. These studies establish that a dexamethasone-inducible family 3A P450 can make an important contribution to rat liver microsomal ifosphamide activation, and suggest that dexamethasone pretreatment might provide a useful approach for modulation of ifosphamide metabolism in order to improve its therapeutic efficacy in cancer patients.
Weber
G F
GF
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
Waxman
D J
DJ
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001711:Biotransformation; D002945:Cisplatin / Q000494:pharmacology; D002994:Clofibrate; D003520:Cyclophosphamide / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D003907:Dexamethasone; D005260:Female; D007069:Ifosfamide / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008956:Models, Chemical; D010634:Phenobarbital; D051381:Rats; D011916:Rats, Inbred F344; D014217:Troleandomycin / Q000494:pharmacology
D000906:Antibodies; D065607:Cytochrome P-450 Enzyme Inhibitors; D003907:Dexamethasone; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D002994:Clofibrate; D002945:Cisplatin; D007069:Ifosfamide; D010634:Phenobarbital