RT Journal Article
SR Electronic
T1 Triethylenethiophosphoramide Is a Specific Inhibitor of Cytochrome P450 2B6: Implications for Cyclophosphamide Metabolism
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 525
OP 530
DO 10.1124/dmd.30.5.525
VO 30
IS 5
A1 James M. Rae
A1 Nadia V. Soukhova
A1 David A. Flockhart
A1 Zeruesenay Desta
YR 2002
UL http://dmd.aspetjournals.org/content/30/5/525.abstract
AB 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 μM thioTEPA when CYP2B6 activity was measured by following the metabolism of 200 μM S-mephenytoin to nirvanol. thioTEPA did not significantly inhibit (<20% at 100 μM) the other isoforms tested (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). thioTEPA seems to be a potent noncompetitive inhibitor of CYP2B6, withKi values of 4.8 ± 0.3 and 6.2 ± 0.7 μM for HLMs and recombinant CYP2B6, respectively, values that are within the plasma concentration range of thioTEPA at therapeutic doses (1.1–18.6 μM). 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. The American Society for Pharmacology and Experimental Therapeutics