Triethylenethiophosphoramide is a specific inhibitor of cytochrome P450 2B6: implications for cyclophosphamide metabolism.

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Rae JM, Soukhova NV, Flockhart DA, Desta Z

Triethylenethiophosphoramide is a specific inhibitor of cytochrome P450 2B6: implications for cyclophosphamide metabolism.

Drug Metab Dispos. 2002 May;30(5):525-30. doi: 10.1124/dmd.30.5.525.

PubMed ID

11950782 [ View in PubMed

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Abstract

Cytochrome P450 2B6 is a genetically polymorphic enzyme that is important in the metabolism of a number of clinically used drugs. This enzyme is not as well studied as other cytochrome P450 (P450) isoforms because of the lack of specific antibodies, probe drugs, and inhibitors. Although recent progress has been made toward specific antibodies and probe drugs, a specific enzyme inhibitor is still lacking. Studies suggest that CYP2B6 plays an important role in the 4-hydroxylation of cyclophosphamide and that this reaction can be inhibited by triethylenethiophosphoramide (thioTEPA). We therefore wished to test the hypothesis that thioTEPA is an inhibitor of CYP2B6. Using human liver microsomes (HLMs) and recombinant P450 enzymes, we demonstrated that thioTEPA is a potent and specific inhibitor of CYP2B6. Enzyme activity was reduced 78.1 +/- 0.2% by 50 microM thioTEPA when CYP2B6 activity was measured by following the metabolism of 200 microM S-mephenytoin to nirvanol. thioTEPA did not significantly inhibit (<20% at 100 microM) the other isoforms tested (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). thioTEPA seems to be a potent noncompetitive inhibitor of CYP2B6, with K(i) values of 4.8 +/- 0.3 and 6.2 +/- 0.7 microM for HLMs and recombinant CYP2B6, respectively, values that are within the plasma concentration range of thioTEPA at therapeutic doses (1.1-18.6 microM). We conclude that thioTEPA is a potent and specific inhibitor of CYP2B6 and that this is the likely mechanism by which thioTEPA inhibits the activation of cyclophosphamide. Furthermore, thioTEPA may prove to be a valuable new tool for the study of this important drug-metabolizing enzyme.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Thiotepa	Cytochrome P450 2B6	Protein	Humans	Unknown	Inhibitor	Details