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

Abstract

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 εM substrate concentration and in the presence of cyclophosphamide (0 to 200 εM), teniposide (0 to 100 εM), vinblastine (0 to 220 εM), etoposide (0 to 200 εM), flavone acetic acid (0 to 1000 εM), or ifosphamide (0 to 200 εM). (S)-Mephenytoin 4-hydroxylation was tested at 60 εM substrate concentration and in the presence of the same drugs as above; vincristine was also tested at 0 to 200 εM. Teniposide competitively inhibited the 4-hydroxylation of (S)-mephenytoin, with a K_i of 12 εM (K_m of the reaction = 65 εM). 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 εM (K_m of the enzyme for the substrate = 12 εM). 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.