Anticancer drugs as inhibitors of two polymorphic cytochrome P450 enzymes, debrisoquin and mephenytoin hydroxylase, in human liver microsomes.
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 microM substrate concentration and in the presence of cyclophosphamide (0 to 200 microM), teniposide (0 to 100 microM), vinblastine (0 to 220 microM), etoposide (0 to 200 microM), flavone acetic acid (0 to 1000 microM), or ifosphamide (0 to 200 microM). (S)-Mephenytoin 4-hydroxylation was tested at 60 microM substrate concentration and in the presence of the same drugs as above; vincristine was also tested at 0 to 200 microM. Teniposide competitively inhibited the 4-hydroxylation of (S)-mephenytoin, with a Ki of 12 microM (Km of the reaction = 65 microM). 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 Ki of 90 microM (Km of the enzyme for the substrate = 12 microM). 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.
Relling
M V
MV
Department of Pharmacology, University of Basel, Switzerland.
Evans
W E
WE
Fonné-Pfister
R
R
Meyer
U A
UA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D005047:Etoposide / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D011110:Polymorphism, Genetic; D013713:Teniposide / Q000494:pharmacology
D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D005419:Flavonoids; D005047:Etoposide; C049328:flavone acetic acid; D013713:Teniposide; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6