Anticancer drugs as inhibitors of two polymorphic cytochrome P450 enzymes, debrisoquin and mephenytoin hydroxylase, in human liver microsomes
Relling, M.V.; Evans, W.E.; Fonné-Pfister, R.; Meyer, U.A.
Cancer Research 49(1): 68-71
1989
ISSN/ISBN: 0008-5472 PMID: 2908853 Document Number: 336241
To identify potential substrates for the debrisoquin and mephenytoin hydroxyation 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 debisoquin polymorphism) was tested at 5 .mu.M substrate concentration and in the presence of cyclophosphamide (0 to 200 .mu.M), teniposide (0 to 100 .mu.M), vinblastine (0 to 220 .mu.M), etoposide (0 to 200 .mu.M), flavoneacetic acid (0 to 1000 .mu.M), of ifosphamide (0 to 200 .mu.M). (S)-Mephenytoin 4-hydroxylation was tested at 60 .mu.M substrate concentration and in the presence of the same drugs as above; vincristine was also tested at 0 to 200 .mu.M. Teniposide competitively inhibited the 4-hydroxylation of (s)-mephenytoin, with a Ki of 12 .mu.M (Km of the reaction = 65 .mu.M). Etoposide and flavoneacetic acid were weaker inhibitors of this reaction. The only agent to inhibit bufuralol hydroxylation was vinblastine, which did so with a Ki of 90 .mu.M (Km of the enzyme for the substrate = 12 .mu.M). We conclude that teniposide and high concentrations of flavoneacetic 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.