Metabolism of cyclophosphamide by purified cytochrome P-450 from microsomes of phenobarbital-treated rats.
Incubation of [3H]-sidechain-labeled and [14C]-C(4)-ring-labeled cyclophosphamide (CPA) with purified cytochrome P-450 from liver microsomes of rats treated with phenobarbital resulted in the production of a major metabolite that contained both labels, was unaffected by diazomethane, possessed high polarity, was identical in TLC and HPLC behavior to a synthetic standard, didechlorodihydroxy -CPA, and was converted to CPA and bis(2-chloroethyl)amine by thionyl chloride . These results indicate that phenobarbital-inducible cytochrome P-450 is able to dechlorinate CPA and may account, in part, for the inability of phenobarbital to enhance the therapeutic activity and toxicity of this important anticancer and immunosuppressive agent.
D000818:Animals; D002250:Carbon Radioisotopes; D055598:Chemical Phenomena; D002621:Chemistry; D002713:Chlorine / Q000378:metabolism; D003520:Cyclophosphamide / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D013461:Sulfur Oxides; D014316:Tritium
D002250:Carbon Radioisotopes; D013461:Sulfur Oxides; D014316:Tritium; C023589:thionyl chloride; D002713:Chlorine; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital