![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 30, Issue 5, 525-530, May 2002
Division of Clinical Pharmacology, Departments of Medicine and
Pharmacology, Georgetown University Medical Center, Washington, DC
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, with
Ki 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.
This article has been cited by other articles:
|
|
 |
|
  J.-W. Zhang, Y. Liu, J.-Y. Zhao, L.-M. Wang, G.-B. Ge, Y. Gao, W. Li, H.-T. Liu, H.-X. Liu, Y.-Y. Zhang, et al. Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate Drug Metab. Dispos., November 1, 2008; 36(11): 2292 - 2298. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Williams, T. Andersson, T. B. Andersson, R. Blanchard, M. O. Behm, N. Cohen, T. Edeki, M. Franc, K. M. Hillgren, K. J. Johnson, et al. PhRMA White Paper on ADME Pharmacogenomics J. Clin. Pharmacol., July 1, 2008; 48(7): 849 - 889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Walsky and R. S. Obach A Comparison of 2-Phenyl-2-(1-piperidinyl)propane (PPP), 1,1',1''-Phosphinothioylidynetrisaziridine (ThioTEPA), Clopidogrel, and Ticlopidine as Selective Inactivators of Human Cytochrome P450 2B6 Drug Metab. Dispos., November 1, 2007; 35(11): 2053 - 2059. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Davies, J. K. Coller, A. A. Somogyi, R. W. Milne, and B. C. Sallustio CYP2B6, CYP2D6, and CYP3A4 Catalyze the Primary Oxidative Metabolism of Perhexiline Enantiomers by Human Liver Microsomes Drug Metab. Dispos., January 1, 2007; 35(1): 128 - 138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. K. L. Kiang, P. C. Ho, M. R. Anari, V. Tong, F. S. Abbott, and T. K. H. Chang Contribution of CYP2C9, CYP2A6, and CYP2B6 to Valproic Acid Metabolism in Hepatic Microsomes from Individuals with the CYP2C9*1/*1 Genotype Toxicol. Sci., December 1, 2006; 94(2): 261 - 271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Hesse, D. J. Greenblatt, L. L. von Moltke, and M. H. Court Ritonavir has minimal impact on the pharmacokinetic disposition of a single dose of bupropion administered to human volunteers. J. Clin. Pharmacol., May 1, 2006; 46(5): 567 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. McCune, L. J. Risler, B. R. Phillips, K. E. Thummel, D. Blough, and D. D. Shen CONTRIBUTION OF CYP3A5 TO HEPATIC AND RENAL IFOSFAMIDE N-DECHLOROETHYLATION Drug Metab. Dispos., July 1, 2005; 33(7): 1074 - 1081. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. N. Bumpus, C. Sridar, U. M. Kent, and P. F. Hollenberg THE NATURALLY OCCURRING CYTOCHROME P450 (P450) 2B6 K262R MUTANT OF P450 2B6 EXHIBITS ALTERATIONS IN SUBSTRATE METABOLISM AND INACTIVATION Drug Metab. Dispos., June 1, 2005; 33(6): 795 - 802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Giraud, A. Tran, E. Rey, J. Vincent, J.-M. Treluyer, and G. Pons IN VITRO CHARACTERIZATION OF CLOBAZAM METABOLISM BY RECOMBINANT CYTOCHROME P450 ENZYMES: IMPORTANCE OF CYP2C19 Drug Metab. Dispos., November 1, 2004; 32(11): 1279 - 1286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Lang, K. Klein, T. Richter, A. Zibat, R. Kerb, M. Eichelbaum, M. Schwab, and U. M. Zanger Multiple Novel Nonsynonymous CYP2B6 Gene Polymorphisms in Caucasians: Demonstration of Phenotypic Null Alleles J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 34 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ramirez, F. Innocenti, E. G. Schuetz, D. A. Flockhart, M. V. Relling, R. Santucci, and M. J. Ratain CYP2B6, CYP3A4, AND CYP2C19 ARE RESPONSIBLE FOR THE IN VITRO N-DEMETHYLATION OF MEPERIDINE IN HUMAN LIVER MICROSOMES Drug Metab. Dispos., September 1, 2004; 32(9): 930 - 936. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Harleton, M. Webster, N. N. Bumpus, U. M. Kent, J. M. Rae, and P. F. Hollenberg Metabolism of N,N',N''-Triethylenethiophosphoramide by CYP2B1 and CYP2B6 Results in the Inactivation of Both Isoforms by Two Distinct Mechanisms J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 1011 - 1019. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Desta, B. A. Ward, N. V. Soukhova, and D. A. Flockhart Comprehensive Evaluation of Tamoxifen Sequential Biotransformation by the Human Cytochrome P450 System in Vitro: Prominent Roles for CYP3A and CYP2D6 J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 1062 - 1075. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Turpeinen, R. Nieminen, T. Juntunen, P. Taavitsainen, H. Raunio, and O. Pelkonen SELECTIVE INHIBITION OF CYP2B6-CATALYZED BUPROPION HYDROXYLATION IN HUMAN LIVER MICROSOMES IN VITRO Drug Metab. Dispos., June 1, 2004; 32(6): 626 - 631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Richter, T. E. Murdter, G. Heinkele, J. Pleiss, S. Tatzel, M. Schwab, M. Eichelbaum, and U. M. Zanger Potent Mechanism-Based Inhibition of Human CYP2B6 by Clopidogrel and Ticlopidine J. Pharmacol. Exp. Ther., January 1, 2004; 308(1): 189 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Miyazawa, A. Sugie, and T. Shimada ROLES OF HUMAN CYP2A6 AND 2B6 AND RAT CYP2C11 AND 2B1 IN THE 10-HYDROXYLATION OF (-)-VERBENONE BY LIVER MICROSOMES Drug Metab. Dispos., August 1, 2003; 31(8): 1049 - 1053. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Ward, J. C. Gorski, D. R. Jones, S. D. Hall, D. A. Flockhart, and Z. Desta The Cytochrome P450 2B6 (CYP2B6) Is the Main Catalyst of Efavirenz Primary and Secondary Metabolism: Implication for HIV/AIDS Therapy and Utility of Efavirenz as a Substrate Marker of CYP2B6 Catalytic Activity J. Pharmacol. Exp. Ther., July 1, 2003; 306(1): 287 - 300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. W. Fan, C. Gu, S. A. Marsh, and J. C. Stevens Mechanism-Based Inactivation of Cytochrome P450 2B6 by a Novel Terminal Acetylene Inhibitor Drug Metab. Dispos., January 1, 2003; 31(1): 28 - 36. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
