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Anticancer Drugs as Inhibitors of Two Polymorphic Cytochrome P450 Enzymes, Debrisoquin and Mephenytoin Hydroxylase, in Human Liver Microsomes¹

Department of Pharmacology [M. V. R., W. E. E., R. F.-P., U. A. M.], Biocenter of the University of Basel, Basel, Switzerland, and University of Tennessee [M. V. R., W. E. E.] and St. Jude Children's Research Hospital [W. E. E.], Memphis, Tennessee 38101

To identify potential substrates for the debrisoquin and mephenytoin hydroxylation polymorphisms, we performed in vitro inhibition studies with human liver microsomes and the respective prototype substrates in the absence and presence of several anticancer drugs. (+)-Bufuralol 1'-hydroxylation (as the prototype reaction for the debrisoquin polymorphism) was tested at 5 M substrate concentration and in the presence of cyclophosphamide (0 to 200 M), teniposide (0 to 100 M), vinblastine (0 to 220 M), etoposide (0 to 200 M), flavone acetic acid (0 to 1000 M), or ifosphamide (0 to 200 M). (S)-Mephenytoin 4-hydroxylation was tested at 60 M substrate concentration and in the presence of the same drugs as above; vincristine was also tested at 0 to 200 M. Teniposide competitively inhibited the 4-hydroxylation of (S)-mephenytoin, with a K_i of 12 M (K_m of the reaction = 65 M). Etoposide and flavone acetic acid were weaker inhibitors of this reaction. The only agent to inhibit bufuralol hydroxylation was vinblastine, which did so with a K_i of 90 M (K_m of the enzyme for the substrate = 12 M). We conclude that teniposide and high concentrations of flavone acetic acid could spuriously alter mephenytoin phenotype determination in cancer patients, and that teniposide deserves further investigation as a possible substrate for the genetically regulated mephenytoin hydroxylase.

¹ Supported by Grant NIH R37-36401, by NIH Cancer Center CORE Grant CA 21765, by the American College of Clinical Pharmacy, by a Centers of Excellence grant from the State of Tennessee, by Swiss National Research Foundation Grant 3.817.87, and by ALSAC.

² To whom requests for reprints should be addressed, at St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38101.

Received 8/ 3/88. Accepted 10/ 4/88.

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